Cortical metabolic changes in the cerebellar variant of multiple system atrophy: A voxel-based FDG-PET study in 41 patients

www.elsevier.com/locate/ynimg NeuroImage 40 (2008) 796 – 801

Cortical metabolic changes in the cerebellar variant of multiple system atrophy: A voxel-based FDG-PET study in 41 patients Phil Hyu Lee,a Young-Sil An,b Seok Woo Yong,c and Seok Nam Yoonb,⁎ a

Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea Department of Nuclear Medicine, Ajou University School of Medicine, Suwon, South Korea c Department of Neurology, Ajou University School of Medicine, Suwon, South Korea b

Received 17 August 2007; revised 17 October 2007; accepted 29 November 2007 Available online 15 December 2007 In addition to neuronal loss in the cerebellum and basal ganglia, recent imaging studies have suggested that cortical involvement may be more extensive in patients with MSA. In this study, we focused on cortical metabolic patterns in 41 patients with MSA-C and 30 controls, using statistical parametric mapping analysis to evaluate whether metabolic derangement in MSA-C patients involved the cortical area and correlated cerebral metabolism with clinical parameters. In patients with MSA-C, SPM analysis revealed that, apart from the expected reduction of FDG-uptake in brainstem–cerebellar area, there was a significant hypometabolism in widespread frontal cortex, including inferior orbitofrontal, rectus, middle and superior frontal, and superior mesiofrontal extending to cingulum, and left inferior parietal cortex. In a subgroup analysis of MSA-C patients, metabolic derangement in the cerebral cortex was visible even in the early stages of MSA-C. In advanced stages, the metabolic derangement tended to evolve into the rostral brainstem and into other cortical areas, including left inferior frontal cortex and right inferior orbitofrontal, right anterior and middle cingulate, and anterior portion of superior mesiofrontal gyri. In correlation analysis, reduced FDG-uptake in orbitofrontal area was most significantly correlated with disease severity and duration, followed by the medial frontal, the dorsal portion of the midbrain, and the cerebellum. Our study demonstrated that there were widespread areas of decreased metabolism in the cerebral cortex and, as the disease progressed, the pattern of metabolic derangement tended to evolve into other frontal areas without significant changes in cerebellar metabolism, suggesting that reduced FDG-uptake in cortical area may be associated with the primary disease process. © 2007 Elsevier Inc. All rights reserved.

Introduction Multiple system atrophy (MSA), a sporadic neurodegenerative disease, usually presents as a combination of parkinsonism, ⁎ Corresponding author. Fax: +82 3 219 5178. E-mail address: [email protected] (S.N. Yoon). Available online on ScienceDirect (www.sciencedirect.com). 1053-8119/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2007.11.055

cerebellar ataxia and autonomic failure, where depending on the predominant features, a parkinsonian type and a cerebellar type of MSA (MSA-C) are separated (Wenning et al., 2004a). Pathologically, MSA is characterized by α-synuclein-positive glial cytoplasmic inclusions (GCI) and neuronal loss, predominantly in the basal ganglia, brainstem, cerebellum, and intermediolateral cell columns of the spinal cord (Burn and Jaros, 2001). Recently, it has been reported that additional involvement of cortical area may be more extensive in patients with MSA than previously thought. These studies were MR-based analyses, including comparisons with controls and longitudinal studies (Brenneis et al., 2007, 2003; Konagaya et al., 2002). In two studies in MSA-C patients, however, results regarding cortical involvement were not consistent. Brenneis and colleagues (2006) reported supratentorial volume loss, while Specht and colleagues (2003) reported that brain atrophy was restricted to the cerebellum and brain stem. Most previous PET studies that have investigated metabolic changes in the brain regions of patients with MSA used the region-of-interest (ROI) method (Gilman et al., 1994; Otsuka et al., 1996). The ROI method, however, selects only those brain regions that are expected to have functional changes, whereas more recently developed voxel-wise analysis, such as the statistical parametric mapping (SPM) method, can detect any brain region with metabolic changes (Ashburner and Friston, 2000). In this study, we focused on cerebral metabolic patterns in a large series of patients with MSA-C, using SPM analysis, to evaluate whether metabolic derangement in MSA-C patients involved cortical areas. In addition, we compared changes in cerebral metabolic patterns between subgroups of patients, depending on disease severity, and correlated cerebral metabolism with disease duration and severity. Materials and methods Subjects We enrolled 41 patients with probable MSA-C and 30 healthy controls. Informed consent was obtained from all subjects. The diagnosis of MSA was made according to the consensus criteria for

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clinical diagnosis of probable MSA (Gilman et al., 1999). Genetic tests for spinocerebellar ataxia types 1, 2, 3, 6, and 7 were negative in all patients. None of patients had symptomatic causes of ataxia, such as infectious disease, multiple sclerosis, paraneoplastic disease, disease of the thyroid, Wilson disease, hypovitaminosis, alcoholism, chronic anticonvulsive therapy, ischemia, or neoplasm. As a measure of disease severity, all patients were evaluated by two independent examiners using the unified multiple system atrophy rating scale (UMSARS) (Wenning et al., 2004b) and UMSARS scores were obtained as the mean of scores performed by two independent investigators (kappa = 0.93). According to the UMSARS, the MSA patients were arbitrarily divided into group A (UMSARS b30), group B (30 V UMSARS b 60), and group C (UMSARS z 60). Statistical comparisons were made between MSA-C and controls, between group A and controls, and between groups A and B, and between groups B and C. FDG PET data acquisition PET/CT data were acquired on a Discovery ST scanner (General Electric Medical Systems, USA). After fasting for at least 4 h, patients received 300 MBq of FDG intravenously. We checked serum glucose-level in all subjects prior to the FDGinjection, and the subjects whose glucose-level exceeds 150 mg/dl were excluded in this study. All subjects were instructed to rest comfortably for 30 min with their eyes closed and ears unplugged and then image acquisition was started. To reduce head movement during scanning, the patients were positioned and maintained using an individually molded head holder. They first had a CT scan (tube-rotation time of 1 s per revolution, 120 kV, 70 mA, 5.0 mm per rotation and an acquisition time of 11.8 s for a scan length of 150.42 mm) and, subsequently, one frame (8 min per frame) of emission PET data was acquired in a three-dimensional mode. PET images were reconstructed by iterative reconstruction (ordered subsets expectation maximization, with one iteration and 32 subsets), using the CT images for attenuation correction. Also, the random correction by singles and model-based scatter correction were applied. Data analysis FDG-PET images were spatially normalized to a standard template provided by SPM2 (Statistical Parametric Mapping 2, Institute of Neurology, University of London, UK) on MATLAB (version 7.1, Mathworks Inc., Natick, MA). A local optimisation of the 12 parameters of an affine transformation was applied to

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spatial normalization. These images were then smoothed with a Gaussian kernel (full-width at half-maximum = 16 mm) to minimize noise and improve between-subject spatial alignment. Appropriate voxel-by-voxel statistical tests were used to evaluate differences in glucose metabolism. First, images of patients with MSA-C were compared with those of controls in a voxel-by-voxel manner, using SPM2 (two-sample t-test). Second, the comparison of glucose metabolism between MSA-C subgroups (groups A, B, C) was performed using a two-sample t-test. Finally, covariance analysis was performed to extract regions whose changes in regional cerebral metabolism correlated significantly with disease duration and UMSARS as determining clinical parameters. Each value of the clinical characteristics was used as a covariate of interest, with using single subject covariates model. Anatomical labeling of significant clusters was performed using automated anatomical labeling SPM toolbox (Tzourio-Mazoyer et al., 2002), which was based to anatomy provided by the Montreal Neurological Institute. Statistical analysis The Mann–Whitney U test and the Kruskal–Wallis analysis were used to compare the means of groups in pairs and in multiple comparisons of demographic characteristics, respectively. Fisher’s Exact Test was used to compare categorical variable. A Bonferroni–Holm method was used to adjust multiple comparisons. P values b 0.05 were deemed statistically significant. The statistical analyses were performed using commercially available software (SPSS, version 13.0). Only regions reaching an FDRcorrected threshold of p b 0.05 were considered to be significant in comparisons between groups and the covariance analyses. Results Demographic characteristics There was no significant difference in mean age (56.9 ± 6.9 versus 58.2 ± 7.2) or female ratio (34% versus 43%) between the patients with MSA-C and control subjects. The mean disease duration and UMSARS in patients with MSA-C were 3.9 ± 2.7 years and 47.5 ± 26.5, respectively. The mean disease duration and UMSARS in the MSA-C subgroups were 1.6 ± 1.4 years and 20.4 ± 6.4 in group A, 4.1 ± 1.4 years and 43.7 ± 8.6 in group B, and 5.9 ± 1.3 years and 78.1 ± 15.1 in group C, respectively (p b 0.001). The details of the demographic characteristics of patients and control subjects are summarized in Table 1.

Table 1 Characteristics of patients with MSA-C, subgroups, and controls

Number Age Female (%) Duration UMSARS Parkinsonism Pyramidal sign

MSA-C

Group A

Group B

Group C

Controls

41 56.96.9 14 (34%) 3.9 ± 2.7 47.5 ± 26.5 15 (37%) 30 (73%)

14 54.6 ± 6.1 3 (21%) 1.6 ± 1.4 20.4 ± 6.4 2 (14%) 4 (29%)

13 56.1 ± 7.1 3 (23%) 4.1 ± 1.4 43.7 ± 8.6 3 (23%) 5 (38%)

14 59.7 ± 7.1 8 (57%) 5.9 ± 1.3 78.1 ± 15.1 10 (71%) 11 (79%)

30 55.2 ± 5.8 13 (43%) – –

p NS,⁎ NS⁎⁎ NS,⁎ 0.049⁎⁎ b0.001⁎⁎ b0.001⁎⁎ b0.05⁎⁎ b0.05⁎⁎

MSA-C: cerebellar variant of multiple system atrophy, UMSARS: unified multiple system atrophy rating scale, group A: UMSARS b30, group B: 30 V UMSARS b 60, group C: UMSARS z60. NS: non-significant, ⁎comparison between MSA-C and controls, ⁎⁎comparison among groups A, B, and C.

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Table 2 Brain area showing significant decrease in glucose metabolism in patients with MSA-C compared to control subjects Voxel-level Coordinate p (FDR-corr) X Y Z b0.001 b0.001 b0.001 b0.001

− 48 46 0 − 22

b0.001

−4

b0.001 b0.001 b0.001 b0.001 b0.005 b0.005

−44 44 − 11 13 22 − 48

Area Side

32 − 12 Left Inferior orbitofrontal gyrus 36 − 18 Right Inferior orbitofrontal gyrus 38 − 26 Bilateral Rectus gyrus 20 48 Left Middle and superior frontal gyrus 32 32 Left Superior mesiofrontal gyrus extended to anterior cingulum − 66 − 36 Left Cerebellum − 72 − 36 Right Cerebellum − 32 − 24 Left Brainstem − 32 − 24 Right Brainstem 26 54 Right Superior frontal gyrus − 50 48 Left Inferior parietal cortex

MSA-C versus controls In patients with MSA-C, SPM analysis revealed large bilateral regions of reduced FDG-uptake affecting almost the entire cerebellum and brainstem, compared with control subjects. Outside the infratentorial regions, a significant reduction in FDG-uptake was observed in widespread frontal cortex areas, including the bilateral inferior orbitofrontal, rectus, left middle and superior frontal, left superior mesiofrontal extending to cingulum (FDR-corr p b 0.001). The right superior frontal and left inferior parietal gyri were also affected (FDR-corr p b 0.005) in patients with MSA-C (Table 2, Fig. 1). Subgroup analysis of MSA-C In group A, compared with controls, FDG-uptake was significantly decreased in the entire cerebellum and brainstem, involving the medullar and pons, but not the midbrain. In the supratentorial area, reduction in FDG-uptake was most evident in the left inferior orbitofrontal, left middle and superior frontal, and left middle cingulate gyri (FDR-corr p b 0.001). Additionally, the left superior mesiofrontal and left inferior parietal cortex (FDRcorr p b 0.005), and right superior frontal and bilateral rectus gyri (FDR-corr p b 0.01) were significantly affected (Table 3, Fig. 2A). In a comparison between the A and B subgroups, no significant metabolic difference was evident. In a comparison between the A and C subgroups, a significant reduction in FDG-uptake was noted in the left inferior frontal cortex (FDR-corr p b 0.01) and right inferior orbitofrontal, right anterior and middle cingulate, and

Table 3 Subgroup analysis in patients with MSA-C Voxel-level Coordinate p(FDR-corr) X Y Z Group A bControl b0.001 − 46 b0.001 −2 b0.001 − 22 b0.001 b0.001 b0.001 b0.001 b0.005 b0.005 b0.01 b0.01

44 − 10 Left −2 40 Left 24 48 Left

− 42 44 −8 7 −4 − 44 0 22

− 76 − 76 − 34 − 34 36 − 44 36 26

Group C bgroup A b0.01 − 52

20

b0.05 b0.05 b0.05 b0.05 b0.05

Area Side

Inferior orbitofrontal gyrus Middle cingulate gyrus Middle and superior frontal gyrus − 34 Left Cerebellum − 34 Right Cerebellum − 33 Left Brainstem − 33 Right Brainstem 32 Left Superior mesiofrontal gyrus 46 Left Inferior parietal cortex − 26 Bilateral Rectus gyrus 54 Right Superior frontal gyrus

6 Left

54 28 − 6 6 32 30 8 22 38 0 54 12 1 − 35 − 17

Inferior frontal trigonum extended to frontal operculum Right inferior orbitofrontal gyrus Right Anterior cingulate gyrus Right Middle cingulate gyrus bilateral Superior mesiofrontal gyrus Bilateral Dorsal midbrain

anterior portion of superior mesiofrontal gyri, as well as the dorsal portion of the midbrain (FDR-corr p b 0.05, Table 3, Fig. 2B). Correlation with disease duration and severity The correlation with UMSARS was strongest in the left inferior orbital gyrus (FDR-corr p b 0.001). Additionally, reduction of FDG-uptake in the right inferior orbital, superior medial, anterior cingulate gyrus, and dorsal portion of midbrain correlated significantly with UMSARS (FDR-corr p b 0.01). The left cerebellum and rectus gyrus also correlated significantly, in a setting with FDR-corr p b 0.05 (Table 4, Fig. 3A). A significant correlation with disease duration was found in the left (FDR-corr p b 0.005) and right (FDR-corr p b 0.01) inferior orbital gyrus, and anterior cingulate gyrus, the dorsal portion of midbrain, and the cerebellum (FDR-corr p b 0.05; Table 4, Fig. 3B). Discussion Although several FDG PET studies in MSA have been reported, most of these investigated regional brain metabolism using visual rating or ROI methods and did not focus on changes in cortical

Fig. 1. Statistical parametric maps showing the spatial distribution of significant metabolic decreases in patients with MSA-C compared with controls. Green and red indicates area with FDR-corr p b 0.001 and p b 0.005, respectively. L: left.

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Fig. 2. Statistical parametric maps (SPM) showing the area of significant metabolic decreases in group A of MSA-C patients compared with controls (A). Green: FDR-corr p b 0.005, Red: FDR-corr p b 0.01. SPM showing significantly decreased metabolism in group C compared with group A of MSA-C (B). Green: FDRcorr p b 0.01, Red: FDR-corr p b 0.05. L: left.

metabolism. Only a few studies have used SPM analysis in patients with MSA, however, these studies included only a small number of patients and focused on metabolic patterns in the differentiation from parkinsonism (Juh et al., 2005). Our SPM analysis of FDG PET images of patients with MSA-C is unique in that we focused on cortical metabolic patterns in a large number of MSA-C patients and the correlation with clinical parameters reflecting disease severity. Our study demonstrated that, apart from the expected reduction of FDG-uptake in brainstem–cerebellar area, there were widespread areas of decreased metabolism, involving the cerebral cortex, in patients with MSA-C. These areas were primarily involved in the frontal cortex, including the dorsolateral frontal, orbitofrontal and medial frontal regions, and additionally in the left parietal region. In the subgroup analysis of MSA-C patients, depending on clinical severity, our study showed that, in addition to cerebello-brainstem involvement, metabolic derangement in the cerebral cortex, including the frontal and parietal areas, was visible even in the early stages of

MSA-C. Metabolic differences between the early and middle stages of MSA-C were not significant. In the advanced stage, however, the metabolic derangement had a tendency to evolve into the rostral brainstem, as well as into other frontal cortical areas, including the left inferior frontal cortex and right orbitofrontal, anterior cingulate, and anterior portion of superior medial frontal cortex. Recent pathological studies evaluating neuronal morphology in detail and the distribution of GCIs have provided evidence of cortical involvement in patients with MSA. Papp and Lantos (1994) reported selective GCI pathology involving the primary sensorimotor area as well as supplementary motor area and anterior cingulate cortex in 12 cases of MSA. Konagaya and colleagues (1999) reported a mildly demented MSA patient with prominent frontal atrophy and pronounced GCI distribution in the motor area of the frontal lobe and the parietal lobe, suggesting that GCIs in the frontal lobe may contribute to cognitive deficits. Additional evidence of cortical involvement in MSA-C patients comes from

Table 4 SPM-correlation analysis Voxel-level p (FDR-corr)

Coordinate X

Y

Z

−48 50 2 4 0 6 −26

26 20 54 30 −28 10 −74

−4 −4 10 28 −9 − 18 − 46

Decrease with disease duration b0.005 −50 b0.01 56 b0.05 −2

28 26 46

−4 −8 16

−28 −54

−9 − 40

Decrease with UMSARS b0.001 b0.01 b0.01 b0.01 b0.01 b0.05 b0.05

b0.05 b0.05

0 −42

Side

Area

Correlation coefficient

Left Right Bilateral Bilateral Bilateral

Inferior orbitofrontal gyrus Inferior orbitofrontal gyrus Superior mesiofrontal gyrus Anterior cingulate gyrus Dorsal midbrain Rectus gyrus Cerebellum

− 0.726 − 0.659 − 0.603 − 0.595 − 0.665 − 0.587 − 0.487

Inferior orbitofrontal gyrus Inferior orbitofrontal gyrus Anterior cingulate gyrus extended to superior mesiofrontal gyrus Dorsal midbrain Cerebellum

− 0.711 − 0.645 − 0.498

Left

Left Right Left

Bilateral

− 0.542 − 0.573

800

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Fig. 3. Correlation with unified MSA rating scale (A, Green: FDR-corr p b 0.001, Red: FDR-corr p b 0.05) and disease duration (B, Green: FDR-corr p b 0.005, Red: FDR-corr p b 0.05). L: left.

a MR-base morphometric study (Brenneis et al., 2006). In the study, there was a volume reduction of cortical gray matter, involving the oribitofrontal, dorsolateral, and medial frontal, parietal, and insular areas. Interestingly, this distribution of cortical atrophy in patients with MSA-C was quite similar to the hypometabolic cortical areas in our study. It is remarkable that, in addition to cerebello-brainstem involvement, cortical hypometabolism involving frontal and parietal areas may occur at an earlier stage of the disease. This is in contrast to a previous study by Taniwaki and colleagues (2002) who reported that there was no hypometabolism in the cerebral cortex in the early stage of MSA, suggesting that the dysfunction in the cerebral cortex appeared only in the later stages of MSA. In the advanced stages of the disease, we found that the pattern of metabolic derangement was more extensive in the frontal area compared with the earlier stages of the disease, whereas cerebellar metabolism was not significantly changed, except in the rostral brainstem area. This suggests that cortical hypometabolism may be associated with the primary disease process, rather than secondary changes due to degeneration of cerebello-cortical projections. In correlation analysis, reduction of FDG-uptake in frontal area was most significantly correlated with disease severity, whereas reduced cerebellar FDG-uptake showed a weak correlation with disease severity. These results also support the primary involvement of the cortical region in the disease process. Although cognitive dysfunction represents an exclusion criterion in the diagnosis of MSA, a few studies have reported frontal lobe dysfunction in patients with MSA, by means of comprehensive neuropsychological testing (Robbins et al., 1992; Robbins et al., 1994). Recently, Burk and colleagues (2006) reported in a study of cognitive function in patients with MSA-C that MSA-C patients were impaired in verbal memory and executive function, suggesting prefrontal dysfunction, although they could not determine the structure responsible for cognitive dysfunction. In our patients with MSA-C, reduced FDG-uptake in cortical area was primarily localized in the prefrontal area, such as orbitofrontal, dorsolateral frontal, and cingulate cortex (anterior and middle). It is well known that these hypometabolic cortical structures are closely involved in working memory and the executive and control functions necessary for performance on neuropsychological tests (Dalley et al., 2004;

Fellows, 2007). Thus, it is postulated that neuronal dysfunction in prefrontal areas, reflected by reduced FDG-uptake in this PET study, may be responsible for cognitive dysfunction of the frontal lobe type in MSA-C. Of the frontal hypometabolic areas, involvement of the rectus gyrus in our study is distinguishing. In fact, some studies have reported volume loss in the rectus gyrus in patients with MSA-C; however, its clinical significance was not mentioned. Regarding that the gyrus rectus is considered to be an extension of the anterior cingulate onto the frontal lobe (Morecraft et al., 1992) and then, be a part of the processing in frontal cognitive function, its reduced FDG-uptake may be related to cognitive dysfunction in MSA-C. In addition, along with the orbitofrontal cortex and anterior cingulate as critical regions involved in the regulation and modulation of affect and emotion, gyrus rectus has also been reported to be part of a circuit that mediates emotional function in humans, such as depression (Ballmaier et al., 2004; Bremner et al., 2002). Cortical hypometabolism in these areas in the present study may point to a structure associated with depressive mood, which is frequently encountered in MSA patients (BenrudLarson et al., 2005). In this study, we did not find any significant change in striatal FDG-uptake in patients with MSA-C. The striatum is another region that is known to exhibit neuronal degeneration in MSA. However, according to MR-based morphometric studies in patients with MSA-C, results regarding striatal involvement have been contradictory. Brenneis et al. (2006) and Specht et al. (2003) found no morphological changes in the striatum, while Minnerop et al. (2007) and Hauser et al. (2006) reported putaminal gray matter loss in patients with MSA-C. It is known that basal ganglia pathology is less prominent in MSA-C than MSA-P, while substantia nigra pathology is severe in both MSA-P and MSA-C (Ozawa et al., 2004). It is possible that putaminal hypermetabolism caused by nigral pathology, may be attenuated due to relatively mildly striatal pathology, resulting in little significant metabolic change of striatum in MSA-C, whereas in MSA-P, the striatal pathology is so severe that cannot reflect putaminal hypermetabolism secondary to nigral pathology, resulting in striatal hypometabolism. In addition, the subcortical localization and the small size of the putamen may make it less suitable for voxel-based analysis than the cerebellum and cortex.

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