Increased intracranial volume in Parkinson's disease

Journal of the Neurological Sciences 239 (2005) 45 – 52 www.elsevier.com/locate/jns

Increased intracranial volume in Parkinson’s disease Katja Krabbe a,*, Merete Karlsborg b, Andreas Hansen a, Lene Werdelin b, Jesper Mehlsen c, Henrik B.W. Larsson a, Olaf B. Paulson a a

Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital, Hvidovre, Kettegaard Alle´ 30, 2650 Hvidovre, Denmark b Department of Neurology, Copenhagen University Hospital, Bispebjerg, Denmark c Department of Physiology, Copenhagen University Hospital, Frederiksberg, Denmark Received 23 February 2005; received in revised form 1 July 2005; accepted 25 July 2005 Available online 11 October 2005

Abstract Background: Parkinson’s disease (PD) and multiple system atrophy (MSA) are neurodegenerative diseases that can be difficult to diagnose and distinguish from each other. Study aims and methods: Patients with PD and MSA and controls were studied with magnetic resonance imaging (MRI) using tissue segmentation and outlining of regions in order to identify regional volume changes that might be useful in the diagnosis of the two diseases. Results: Patients with PD had significantly larger intracranial volumes (ICVs) and significantly smaller putaminal and sustantia nigra volumes than controls. MSA patients had significantly smaller substantia nigra and caudate volumes than controls but normal intracranial volume. In both patient groups there was a further trend towards smaller amygdala volumes. Discussion: Increased ICV in PD patients is a new finding that may be explained by genetic factors or compensatory responses to early CNS damage. Atrophy of the amygdala in MSA patients has not been demonstrated with MR before. It might explain why these patients can have hyposmia. The putaminal atrophy found in the PD group may be a trait of the later stages of PD. Segmentation of the substantia nigra can be a useful aid in the diagnosis of PD and MSA. D 2005 Elsevier B.V. All rights reserved. Keywords: Parkinson’s disease; Multiple system atrophy; Magnetic resonance imaging; Tissue segmentation; Intracranial volume

1. Introduction Parkinson’s disease (PD) and multiple system atrophy (MSA) are neurodegenerative diseases that share common symptoms and that, especially in the early stages of the diseases, can be difficult to diagnose differentially. Tremor, rigidity and bradykinesia are features characteristic of PD, but these traits may also be seen in MSA. Symptoms that may distinguish MSA from PD are autonomic failure, cerebellar signs, corticospinal tract dysfunction and poor response to levodopa therapy. Furthermore, Parkinson symptoms in MSA are most often symmetric at onset and dominated by bradykinesia and rigidity.

* Corresponding author. Tel.: +45 36 32 29 76; fax: +45 36 47 03 02. E-mail address: [email protected] (K. Krabbe). 0022-510X/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2005.07.013

Clinically, there are two subtypes of MSA: MSA with mainly parkinsonian features (MSA-P) and MSA where cerebellar symptoms predominate (MSA-C). Although they share common features, PD and MSA are different pathological entities. MSA is characterized by a-synuclein-positive oligodendroglial cytoplasmic inclusions as first described in 1989 by Papp et al. [1]. Varying degrees of cell loss and/or gliosis are found in basal ganglia, thalamus, substantia nigra and other brain stem nuclei, in transverse pontine fibers and in the spinal cord [2 – 4]. Cell loss may also be seen in frontal, parietal and cerebellar cortex and in frontal and cerebellar white matter [3 –6]. The hallmark lesions of PD are the loss of pigmented substantia nigra neurons and the presence of Lewy bodies. The number of pigmented large neurons in the pars compacta of the substantia nigra is reduced to fewer than

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50% of that seen in young adults. Neuronal loss can also be seen in many other brainstem nuclei, globus pallidus, hypothalamic nuclei, hippocampus and amygdala [7– 10]. Intraneuronal and extracellular Lewy bodies are found mostly in brain regions where neuronal loss is present [7]. Pathology studies indicate that cell loss is more severe and widespread in MSA than in PD. This is in accord with recent MR volumetric studies that have shown reduced striatal, brainstem, insular, cerebellar and frontal cortical volumes in MSA patients compared with PD patients [11– 13]. The present study used tissue segmentation to analyze MR images from patients with PD and MSA in order to measure regional intracranial volumes. The aim of this work was to investigate whether disease induced regional volume changes could be measured and used in the diagnosis of the diseases and used to differentiate between them.

2. Subjects and methods 21 patients with idiopathic Parkinson’s disease, 10 patients with MSA-P and 19 healthy age matched controls were recruited for the present study. All subjects gave consent after written and oral explanation of study aims and procedures. The study was approved by the Copenhagen and Frederiksberg County scientific ethical committees. 2.1. Inclusion and exclusion criteria Subjects had to be 18 years old or above and nondemented. Patients with other neurological diseases than parkinsonian syndromes and subjects with a history of neurological disease or drug or alcohol abuse were excluded. Subjects with severe claustrophobia or other factors incompatible with MR scanning were also excluded.

2 could not be scanned due to severe kyphosis of the thoracic spine. Controls were recruited through advertisements in local newspapers. 2.3. Clinical examination All patients were examined clinically by a trained neurologist specialized in movement disorders. Diagnosis according to the clinical research criteria for PD [14] and MSA [15] was determined. Disease severity was rated with the Hoehn and Yahr (H&Y) scale [16] and the motor section of the Unified Parkinson’s Disease Rating Scale (UPDRS) in all patients. Due to patients’ reluctance to be off medication, only 10 of the patients with PD and 5 of the patients with MSA were rated in the off state after at least 12 h off medication. All subjects were questioned about their educational background and a mini mental state examination (MMSE) [17] was performed. Height and blood pressure were measured. Clinical measures for patients and controls are shown in Table 1. 2.4. Imaging protocol MR imaging was performed using a Siemens Magnetom Vision 1.5 T scanner (Siemens AG, Erlangen, Germany) utilising a standard head coil. Two whole-brain image series were acquired: 1: T1 weighted gradient echo (MPRAGE) sequence in the sagittal plane with TR = 9.7 ms, TE = 4 ms, flip angle = 12-, FoV = (250  250) mm, matrix = (256  256) and slab thickness = 170 mm giving a voxel size of (0.98  0.98  1.00) mm. 2: Proton density (Pd) and T2 weighted spin-echo sequence with TR = 5000 ms, TE = 80/20 ms, FoV = 230 mm, matrix (256  256), 52 slices and slice thickness 4 mm giving a voxel size of 0.9  0.9  4 mm. The slices were oriented paracoronally perpendicular to the intercommi-

2.2. Patients and controls

Table 1 Clinical data of subjects

Patients were recruited from the outpatient clinic at the department of neurology at Copenhagen University Hospital, Bispebjerg. PD patients fulfilled the diagnostic criteria for possible (3) or probable (18) Parkinson’s disease as described by Gelb et al. [14]. MSA patients fulfilled the diagnostic criteria for possible (3) or probable (7) MSA described by Gilman et al. [15] and exhibited predominantly parkinsonian features (MSA-P). Initially, 30 patients with PD were asked to participate in the study and 24 of these agreed. Three of these could not cooperate during MRI due to claustrophobia. Of the 18 patients with MSA who were asked, 14 gave consent to participate in the study. Two of these had claustrophobia and

Diagnosis

PD

MSA

Controls

Number of subjects Gender, males; females

21 15; 6

10 8; 2

19 14; 5

Mean Std. Mean Std. Mean Age (years) 57.5 9.6 61.6 9.6 58.4 Height (cm) 176.2 8.6 173.1 8.5 173.4 Education (years)* 13.4 3.8 11.4 3.7 14.3 MMSE score 28.2 1.8 28.6 1.1 29 H&Y score** 2.3 1 3.1 0.9 UPDRS (motor part)a 39 21 34 20 Duration of disease (years)** 8.1 5.5 4.8 1.8

Std. 11.5 12.4 3 0.8

a Only rated in 10 patients with PD and 5 patients with MSA. * Significant difference between MSA patients and controls ( p < 0.05). ** Significant difference between patient groups ( p < 0.05).

K. Krabbe et al. / Journal of the Neurological Sciences 239 (2005) 45 – 52

sural line located on the mid-brain slice of the MPRAGE sequence. Dual spin-echo images were used for tissue segmentation, MPRAGE images were used to improve visualization of structural boundaries. 2.5. Image analysis The same anatomist who was blinded to the clinical diagnosis, age and gender of the subject analyzed all image series using a previously described method [18]. The method involves isolation of brain voxels, three-dimensional spatial filtering of the matrix of pixel values representing the brain voxels, reslicing of the volume to a

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standard orientation, tissue segmentation by voxel classification and designation of anatomical regions. The steps of the analysis are semiautomated involving human intervention at certain points. Image series from each subject are analyzed individually and spatial normalization is thus not applied. Segmented brain images from a 58-year-old man with PD are shown in Fig. 1. 2.6. Statistical methods The following clinical measures were compared between groups using t-tests for independent samples: age, height, length of education, MMSE score, H&Y

Fig. 1. Segmented brain images from a 58-year-old man with Parkinson’s disease.

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than MSA patients. MSA patients had significantly fewer mean years of education than controls whereas PD patients were matched with both controls and MSA patients on this measure. Table 2 summarizes effects of diagnosis, age, gender and ICV; these effects and results of contrast analysis and correlations between clinical findings and regional volumes are discussed below.

score, UPDRS and duration of disease. The sum of each region on the two sides was used for the statistical analysis of the regional volumes. The volumes of the following structures were analyzed: Cerebellar grey and white matter, lateral and third ventricles, brainstem grey and white matter, caudate nucleus, putamen, thalamus, substantia nigra, hippocampus, amygdala, frontal lobe grey matter and supratentorial and infratentorial total intracranial volume. Univariate analysis of variance was performed with the regional volume as the dependent variable and diagnosis, sex, age and intracranial volume (supratentorial or infratentorial) as predictors. Intracranial volumes were left out as predictors in the analysis of supratentorial and infratentorial intracranial volume. For structures where a significant effect of diagnosis was found a post hoc test was performed for each patient group in order to analyze the relation between H&Y score and the regional volume. Univariate analysis of variance was used with the regional volume as the dependent variable and H&Y score and total intracranial volume (supratentorial or infratentorial) as predictors. A similar analysis was carried out with duration of disease replacing H&Y as predictor. The level of significance was set at p  0.05.

3.1. Age effects Age was significantly negatively correlated with grey matter volume in all cortical structures except the amygdala. No significant correlation with age was found in any subcortical structure. In the putamen there was however a trend towards negative correlation between age and volume ( p = 0.094). There was a positive correlation between ventricular volume and age ( p = 0.001). The finding that age mainly affects cortical grey matter structures and CSF volume is in agreement with previous studies [18,19]. However a certain effect of age on the putamen has been described in both MR and pathology studies [20,21]. 3.2. Gender effects Males had significantly larger supratentorial and infratentorial intracranial volumes than females ( p = 0.000 for both). For the other measures, where ICV was added as a covariate in the analyses, no significant effects of gender were found. Gender effects thus appear to be largely accounted for by differences in ICV.

3. Results and discussion Clinical measures for each group are shown in Table 1. There were no group differences in age, gender, MMSE score or height. PD patients had significantly longer mean disease duration and significantly lower mean H&Y score

Table 2 Absolute volumes of regions and p-values from analysis of variance Structure/Diagnosis Volume in cm3, mean (standard deviation) PD

MSA

Controls

Cerebellar grey 86.61 (11.11) 80.08 (14.79) 82.09 (14.19 Cerebellar white 70.49 (14.00) 65.69 (19.23) 60.99 (9.42) Ventricles 45.44 (21.88) 50.59 (20.21) 44.83 (27.75) Brainstem grey 3.88 (1.01) 3.98 (1.45) 3.52 (0.74) Brainstem white 16.10 (3.41) 14.00 (3.34) 14.06 (2.58) Caudate nucleus 6.55 (0.80) 6.21 (0.88) 6.61 (0.81) Putamen 7.01 (1.02) 7.28 (1.72) 8.13 (1.22) Thalamus 8.86 (0.90) 8.14 (1.97) 8.44 (0.93) Substantia nigra 0.44 (0.20) 0.34 (0.18) 0.74 (0.20) Hippocampi 5.18 (1.48) 7.90 (1.95) 5.45 (1.60) Amygdala 6.56 (1.61) 7.49 (1.34) 7.51 (1.99) Frontal grey 152.03 (29.92) 144.97 (21.97) 153.33 (18.49) Frontal White 246.55 (44.60) 235.71 (46.53) 223.00 (41.36) Supratentorial ICV 1321.83 (155.35) 1330.67 (157.01) 1249.39 (150.63) Infratentorial ICV 214.66 (25.33) 210.12 (27.50 196.39 (23.12) n.s: p > 0.1. trend: 0.05 < p  0.1. * 0.01 < p  0.05. ** 0.000 < p  0.01 *** p  0.000.

Analysis of variance

Contrasts

Diagnosis Gender Age ICV PD vs. C

MSA vs. C

PD vs. MSA

n.s. n.s. n.s. n.s. n.s. n.s. ** n.s. *** n.s. trend n.s. n.s. n.s. **

MSA < C, MSA > C, MSA > C, MSA > C, MSA < C, MSA < C, MSA < C, MSA < C, MSA < C, MSA > C, MSA < C, MSA < C, MSA > C, MSA > C, MSA > C,

PD > MSA, PD > MSA, PD < MSA, PD < MSA, PD > MSA, PD > MSA, PD < MSA, PD > MSA, PD > MSA, PD < MSA, PD < MSA, PD > MSA, PD > MSA, PD < MSA, PD > MSA,

trend n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. *** ***

*** n.s. ** n.s. n.s. n.s. trend n.s. n.s. *** n.s. ** n.s. n.s. n.s.

n.s. ** * n.s. *** ** n.s. n.s. n.s. n.s. n.s. * ***

PD > C, PD > C, PD > C, PD > C, PD > C, PD < C, PD < C, PD > C, PD < C, PD < C, PD < C, PD < C, PD > C, PD > C, PD > C,

n.s. n.s. n.s. n.s. n.s. n.s. ** n.s. *** n.s. trend n.s. n.s. * **

n.s. n.s. n.s. n.s. n.s. * trend n.s. *** n.s. trend n.s. n.s. n.s. n.s.

n.s. n.s. n.s. n.s. trend n.s. n.s. n.s. n.s. trend n.s. n.s. n.s. n.s. n.s.

K. Krabbe et al. / Journal of the Neurological Sciences 239 (2005) 45 – 52

3.3. Effects of disease 3.3.1. Substantia nigra Overall diagnosis effect was significant for substantia nigra ( p = 0.000) and contrast analysis showed significantly smaller substantia nigra volumes in both PD and MSA patients vs. controls ( p = 0.000 for both). No correlation was found between the volume of substantia nigra and H&Y or duration of disease in either of the patient groups. Cell loss in the substantia nigra is one of the main features of PD and MSA. In Parkinson’s disease, 48% of neurons in the pars compacta are already lost when symptoms appear and after symptom onset there is an exponential loss of pigmented neurons with a 45% loss in the first decade [22]. In MSA proven by pathology, there is cell loss in the substantia nigra in over 90% of cases [4]. In a previous MR study significant narrowing of the pars compacta of the substantia nigra was found on axial T2 weighted images in patients with PD and MSA compared to controls. No differences were found between patient groups [23]. In the present study, we use the fact that the pars compacta of the substantia nigra is a grey matter structure surrounded by either white matter or pigmented grey matter which makes it easy to segment and circumscribe. The volume of the pars compacta of the substantia nigra was significantly smaller in patients than in controls but there was some overlap between groups. We found no significant difference between the patient groups. Segmentation of the substantia nigra can be a useful aid to the diagnosis of PD and MSA but the method is not appropriate for differential diagnosis between the two diseases. 3.3.2. Putamen Overall diagnosis effect was significant for putamen ( p = 0.009) and contrast analysis showed that putamen was significantly smaller in PD patients than in controls ( p = 0.003). In the MSA group there was a trend towards smaller volumes than in the control group ( p = 0.052). There were no correlations between the volume of putamen and H&Y or duration of disease in either of the patient groups. Atrophy of the putamen in MSA has been well described in pathology and imaging studies [3,4,6,11,12,24 – 26] whereas there has been more controversy about putaminal volume in PD. In one study of the neuropathology of PD decreased density of striatal nerve cell populations was found [27] whereas no difference in striatal volumes or number of nerve cells between PD patients and controls was found in another [28]. There were no separate measures for putamen and caudate in these two studies. In one MR study, caudate, putamen and thalamic nuclei volumes were significantly smaller in PD patients than

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in controls [29] whereas no differences in putaminal volume were found between PD patients and controls in other studies [11,12,24]. Putaminal atrophy may be a characteristic of the later stages of both diseases and this explains why the finding was significant in our PD group where mean disease duration was relatively long, but not in the MSA group where disease duration was much shorter. 3.3.3. Caudate nucleus Overall effect of diagnosis was not significant but contrast analysis showed significantly smaller caudate volumes in MSA patients than in controls ( p = 0.045). There was no correlation between caudate nucleus volume and H&Y or duration of disease in either of the patient groups. In a review of 203 cases of MSA the caudate nucleus was only found normal in 45% of cases whereas there was mild to severe gliosis and/or cell loss in the remaining cases [4]. Decreased volume of caudate and putamen in MSA patients compared with controls has also been demonstrated in MR studies [11,12]. Atrophy of the caudate nucleus in PD patients has been demonstrated in two MR studies [11,29] but evidence of caudate atrophy from pathology studies is scarce and is only a possible finding in the previously mentioned study of striatal volume in PD [27]. 3.3.4. Thalamus Overall effects of diagnosis and contrast analysis were not significant. In the previously mentioned review of 203 cases of MSA [4] cell loss and/or gliosis was graded on a fourpoint scale and scores for different structures were listed. The thalamus was found to be normal in most cases, but in 22% of cases there was mild to severe involvement of the thalamus. Neuropathology studies of the thalamus in PD have shown a non-significant nerve cell loss in the anterior paraventricular and anterior ventral lateral nuclei in PD [30]. Thalamic cell loss thus seems to be absent or sparse in the two diseases and most probably not measurable with MR. In one MR study atrophy of the thalamus in PD was demonstrated [29] whereas no signs of thalamic atrophy in PD or MSA were found in another [11]. 3.3.5. Cerebellum Overall effects of diagnosis and contrast analysis of cerebellar grey and white matter volumes were not significant. Studies of neuropathology in MSA have shown loss of Purkinje cells in the cerebellar hemispheres and vermis, degeneration of the dentate nucleus and white matter loss in the cerebellar hemispheres and middle cerebellar peduncles [3,4,6,26]. Correspondingly MR studies in MSA have shown loss of cerebellar grey matter in hemispheres and vermis and white matter loss in cerebellar

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hemispheres and superior and middle cerebellar peduncles. Furthermore dilatation of fourth ventricle and atrophy of dentate nucleus have been described [12,13,24,25,31]. In PD no changes are found in the cerebellum in pathology or MR studies [7,11,24]. Our lack of findings may be due to the fact that our method measures the entire grey or white matter of the cerebellum and regional cerebellar changes may not be detectable with this method. 3.3.6. Hippocampus and amygdala For the amygdala there was a trend towards an overall effect of diagnosis ( p = 0.082) and contrast analysis showed a trend towards smaller volumes in both PD and MSA patients than in controls ( p = 0.053 and p = 0.060 respectively). For the hippocampus the overall effect of diagnosis was not significant but contrast analysis showed a trend towards smaller hippocampal volume in the PD group than in the MSA group ( p = 0.058). The mean hippocampal volume for the control group was lying between that of the two patient groups. Mesial temporal lobe atrophy is well documented in PD. MR volumetric studies of the hippocampus have shown decreased hippocampal volume in patients with PD compared to controls and correlation between hippocampal volume and recognition memory scores and scores in the MMSE have been demonstrated [32,33]. The amygdala volumes were not measured in these studies. In studies of the neuropathology in PD, the volume of the mesial temporal lobe has been measured. In one study significant volume loss in the mesial temporal lobe was found [8]. Hippocampus and amygdala were not examined separately so it is not known whether one or both structures were responsible for the significance. In a study of the neuropathology of the amygdala in PD a 20% reduction of total amygdala volume in patients compared to controls was found [9]. Volume loss was due to a 30% reduction in volume and number of neurons in the corticomedial complex. The cortical nucleus, which is a part of the corticomedial complex receives afferent fibers from the olfactory bulb and has projections to the olfactory cortices. This finding may account for the olfactory deficits previously described in PD. In a study of olfactory function in Parkinsonian syndromes, seven of the eight MSA patients included in the study were hyposmic [34]. Furthermore PD patients had significantly lower olfactory sensitivity and significantly lower scores for odour discrimination, thresholds and identification than patients with MSA. Minimal neuronal cell loss in the amygdala in MSA has only been described in a few patients before [6] and has not been demonstrated in MR studies but the finding may explain why also patients with MSA are hyposmic. Cell loss in the amygdala may also in part explain the autonomic symptoms seen in MSA. Subnuclei of the amygdala are part of a central autonomic network receiving afferents from brain stem nuclei involved in cardiovascular control and sending efferents to brain stem

autonomic control sites [35]. Loss of neurons in brain stem nuclei may however also be responsible for autonomic symptoms seen in MSA [2,36]. 3.3.7. Brainstem Overall group differences in grey and white matter of the brainstem were not significant, but contrast analysis showed a trend towards smaller brainstem white matter in MSA than in PD patients ( p = 0.073). This may reflect the loss of transverse pontine fibers and degeneration of pyramidal tracts seen in MSA. Neuropathology studies of PD [10] and MSA [2– 4,6,26] show atrophy of numerous brainstem nuclei and in MSA also white matter tracts are affected [3,4,6]. MR studies of patients with MSA-P have also shown atrophy of the brainstem [12,24,25,31] and in some of these studies it seems likely that signal change and atrophy are due to loss of transverse pontine fibers [24,25]. 3.3.8. Frontal lobe Analysis of variance and contrast analysis of frontal lobe grey and white matter showed no significant differences between groups. In a neuropathology study of patients with PD no loss of neurons was found in the frontal lobes of patients compared with controls [37]. In one MR study of patients with PD cortical grey matter atrophy has been demonstrated [29] whereas other MR studies have shown no atrophy of the frontal lobes [11,32,38]. Neuropathology studies in MSA have shown neuronal loss in frontal cortex and loss of myelinated fibers and astrocytosis in frontal white matter [3 –6]. Some investigators have been able to demonstrate this atrophy with MR [11,31,39] whereas others have not [23,25]. The reason why frontal atrophy may be difficult to detect is that only small parts of the cortex are affected as demonstrated in one of the MR studies [11]. Patients with MSA-P had atrophy in primary sensorimotor cortex, supplementary motor area (SMA), insular cortices and middle frontal gyrus (prefrontal) bilaterally compared to controls and patients with PD. Furthermore, they had atrophy in right premotor cortex. The frontal lobe is the biggest of the cerebral lobes and in this study we measure the entire frontal lobe grey and white substance. If our MSA patients had atrophies in small regions of the frontal lobes we may have been unable to demonstrate them. 3.3.9. Ventricles For the ventricles analysis of variance and contrast analysis showed no significant differences between groups. Ventricular enlargement can reflect both grey and white substance loss in various regions in the brain [40]. In PD lateral and third ventricles have been found normal in an MR study [38]. In one MR study patients with MSA-P had enlargement of lateral and third ventricles compared to controls and patients with PD [11]. This corresponds well

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with the finding of widespread areas of atrophy in the MSA patients in the study. Similarly, we would not expect any significant enlargement of ventricles in the present study since atrophy elsewhere in our patient groups was more limited. 3.3.10. Intracranial volumes Overall diagnosis effect was significant for infratentorial ICV ( p = 0.008) and contrast analysis showed significantly larger supratentorial and infratentorial ICVs in PD patients than in controls ( p = 0.045 and p = 0.002 respectively). In the PD group, this was due to non-significant increases in the amount of total grey matter and white matter volume supratentorially and a non-significant increase in all three tissue classes infratentorially. This has not been demonstrated before and clearly requires replication to assess its reliability. The etiology of PD remains unknown but both genetic and environmental factors may be involved [41 –45]. Since intracranial volume most likely does not grow in adulthood, it is likely that the group differences arise during development of the CNS. The factors that cause PD thus seem to influence the brain early in life, maybe even in utero. Although the present study provides no evidence regarding the mechanisms leading to increased brain volume in PD, the effect could be due to genetic factors or compensatory responses to early CNS damage. 3.3.11. General considerations and future perspectives Many of our findings confirm previous findings and correspond well with clinical findings in the two diseases. In our approach, we chose a reliable, established segmentation method that could provide information about cortical and subcortical brain regions and intracranial volume [18]. Its major drawback is that it is time consuming and does not give information about subregions of the cerebral lobes. For group differences in small cortical regions VBM is more useful but registration problems may reduce the accuracy of volumes of subcortical structures. New methods developed by Fischl et al. can detect subtle changes in cortical thickness [46] and automatically assign neuroanatomical labels to cortical regions [47]. Furthermore a method for automated brain segmentation and labeling of cortical and subcortical structures has been presented [48]. These promising methods may be useful in future studies of early stages of parkinsonism where small regional brain volume changes can be difficult to detect.

4. Conclusion The most important result of this study is the finding of increased intracranial volume in PD which has not been demonstrated before. Since the ICV does not grow in

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adulthood the effect could be due to genetic factors or compensatory responses to early CNS damage. In addition there were other new results: the amygdala seems to be atrophic in MSA and this may explain why these patients may have hyposmia. Atrophy of the putamen may occur in the later stages of PD. Segmentation of the substantia nigra proved useful as an aid in the diagnosis of PD and MSA. Generally our findings confirmed results from previous MR and pathology studies and explained clinical symptoms. Acknowledgements We would like to thank Professor Terry Jernigan, UCSD, California, for the critical revision of the manuscript. This study has been supported financially by the Danish Medical Research Council, Research Foundation of the Danish Medical Association, Dagmar Marshall Foundation, Lily Benthine Lund Foundation, Danish Parkinson Association and Engineer Poul Lundbeck and Wife’s Foundation for Promotion of Radiology in Denmark. References [1] Papp MI, Kahn JE, Lantos PL. Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy – Drager syndrome). J Neurol Sci 1989;94(1 – 3):79 – 100. [2] Benarroch EE, Smithson IL, Low PA, Parisi JE. Depletion of catecholaminergic neurons of the rostral ventrolateral medulla in multiple systems atrophy with autonomic failure. Ann Neurol 1998; 43(2):156 – 63. [3] Konagaya M, Sakai M, Matsuoka Y, Konagaya Y, Hashizume Y. Multiple system atrophy with remarkable frontal lobe atrophy. Acta Neuropathol (Berl) 1999;97(4):423 – 8. [4] Wenning GK, Tison F, Ben Shlomo Y, Daniel SE, Quinn NP. Multiple system atrophy: a review of 203 pathologically proven cases. Mov Disord 1997;12(2):133 – 47. [5] Spargo E, Papp MI, Lantos PL. Decrease in neuronal density in the cerebral cortex in multiple system atrophy. Eur J Neurol 1996;3: 450 – 6. [6] Su M, Yoshida Y, Hirata Y, Watahiki Y, Nagata K. Primary involvement of the motor area in association with the nigrostriatal pathway in multiple system atrophy: neuropathological and morphometric evaluations. Acta Neuropathol (Berl) 2001;101(1):57 – 64. [7] Cornford ME, Chang L, Miller BL. The neuropathology of parkinsonism: an overview. Brain Cogn 1995;28(3):321 – 41. [8] Double KL, Halliday GM, McRitchie DA, Reid WG, Hely MA, Morris JG. Regional brain atrophy in idiopathic Parkinson’s disease and diffuse Lewy body disease. Dementia 1996;7(6):304 – 13. [9] Harding AJ, Stimson E, Henderson JM, Halliday GM. Clinical correlates of selective pathology in the amygdala of patients with Parkinson’s disease. Brain 2002;125(Pt 11):2431 – 45. [10] Jellinger KA. Pathology of Parkinson’s disease. Changes other than the nigrostriatal pathway. Mol Chem Neuropathol 1991;14(3):153 – 97. [11] Brenneis C, Seppi K, Schocke MF, Muller J, Luginger E, Bosch S, et al. Voxel-based morphometry detects cortical atrophy in the Parkinson variant of multiple system atrophy. Mov Disord 2003; 18(10):1132 – 8. [12] Schulz JB, Skalej M, Wedekind D, Luft AR, Abele M, Voigt K, et al. Magnetic resonance imaging-based volumetry differentiates idiopathic

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