PSP as Distinguished from CBD, MSA-P and PD by Clinical and Imaging Differences at an Early Stage

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1 ORIGINAL ARTICLE PSP as Distinguished from CBD, MSAP and PD by Clinical and Imaging Differences at an Early Stage Tomoko Kurata 1, Satsuki Kametaka 1, Yasuyuki Ohta 1, Nobutoshi Morimoto 1, Shoko Deguchi 1, Kentaro Deguchi 1, Yoshio Ikeda 1, Yoshiki Takao 2,TaiseiOhta 3, Yasuhiro Manabe 4, Shuhei Sato 5 and Koji Abe 1 Abstract Objective Because it is often difficult to precisely diagnose and distinguish progressive supranuclear palsy (PSP) from corticobasal degeneration (CBD), multiple system atrophyparkinsonism (MSAP) and Parkinson s disease (PD) at the onset of the disease, we compared the patients and clarified the features of these diseases. Methods We compared 77 PSP, 26 CBD, 26 MSAP and 166 PD patients from clinical and imaging points of view including cerebral blood flow (CBF) in the frontal eye field. Results The clinical characteristics of PSP were supranuclear gaze disturbance, optokinetic nystagmus (OKN) impairment and falls at the first visit. On head MRI, midbrain tegmentum atrophy was much more frequently detected in PSP than in all of the other groups. Hearttomediastinum average count ratio (H/M) in iodine123 metaiodobenzyl guanidine ( 123 IMIBG) myocardial scintigraphy was not decreased in PSP, CBD, MSAP and PDYahr 1 (1), but patients of PD2, 3, 4 and 5 showed a significant decrease compared with the PSP group. The CBF in the left frontal eye field of PD3 group and that in right frontal eye field of PD3 and PD4 groups were lower than that of PSP group, although other groups showed a tendency without a significant decrease compared with PSP group. Conclusion PSP is distinguishable from CBD, MSAP and PD even at the early stage with extraocular movement (EOM) disturbance, falls, atrophy of the midbrain tegmentum, and H/M in 123 IMIBG myocardial scintigraphy, and the reduction of CBF in area 8 could serve as a supplemental diagnostic method for distinguishing PSP from PD3 or PD4. Key words: ethyl cysteinate dimmersingle photon emissioncomputed tomography, frontal eye field, multiple system atrophy, Parkinson s disease, progressive supranuclear palsy () () Introduction Abnormalities of tau and αsynuclein have been described in a variety of neurodegenerative diseases, all of those show parkinsonism such as tremor, bradykinesia, rigidity and gait impairment. Main tauopathies with parkinsonism are progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). PSP was first described by Steele, Richardson, and Olszewski in 1964 as a clinical entity that showed supranuclear ophthalmoplegia, dystonia, rigidity of the neck and upper trunk, pseudobulbar palsy, and dementia (1). CBD was first described in 1968 as corticodentatonigral degeneration with neuronal achromasia (2), which shows late middle age onset, progressive asymmetric rigidity, apraxia, tremor, and cortical and extrapyramidal dysfunction (3). Department of Neurology, Okayama University Graduate School of Medicine and Dentistry, Japan, Department of Neurology, Kurashiki Heisei Hospital, Japan, Department of Neurology, Ota Memorial Hospital, Japan, Department of Neurology, National Hospital Organization Okayama Medical Center, Japan and Department of Radiology, Okayama University Graduate School of Medicine and Dentistry, Japan Received for publication June 6, 2011; Accepted for publication July 28, 2011 Correspondence to Dr. Koji Abe, toko11@cc.okayamau.ac.jp 2775

2 On the other hand, the main synucleinopathies with parkinsonism are Parkinson s disease (PD) and multiple system atrophy with parkinsonism (MSAP). PD is the most common cause of parkinsonism; it was originally referred to in 1817 by James Parkinson in An essay on the shaking palsy as reoccurrence of autonomic regulatory disorders (4), and it is mainly characterized by motor symptoms such as resting tremor, bradykinesia, rigidity, and postural instability. MSA was first introduced in 1969 (5), and MSA P is recognized as a certain type of MSA showing predominant parkinsonism, autonomic failure, and poor levodopa (L DOPA)response (6). The clinical differentiation among PSP, CBD, MSAP and PD is of decisive importance from two important points of the response to therapy and the respective prognosis. At disease onset, it is particularly difficult to precisely diagnose and distinguish these diseases presenting with an akineticrigid syndrome. We previously reported that Zscores of ethyl cysteinate dimmersingle photon emission computed tomography (ECDSPECT) in the frontal eye field are significantly lower in PSP than in pure akinesia, and they are very useful for distinguishing these similar disorders and their clinical differences (7). Our previous study suggested the usefulness of such comparisons with clinical characteristics and image analysis for relevant tauopathies and synucleinopathies. In order to clarify the features of PSP, CBD, MSAP and PD within a short period from the first hospital visit, we compared patients with these tauopathies and synucleinopathies in the present study from clinical and imaging points of view including cerebral blood flow (CBF) in the frontal eye field. Materials and Methods For this study, 77 clinically diagnosed cases of PSP, 26 cases of CBD, 26 cases of MSAP, and 166 cases of PD were enrolled. The clinical diagnosis was based on the clinical criteria of the National Institute of Neurologic Diseases and Stroke for PSP and the concept advocated by Boeve et al (2003) for CBD, and the second consensus statement on the diagnosis of MSA (3) for MSAP, and Queen Square Brain Bank criteria for PD. The severity of PD was assessed using the Hoehn and Yahr scale (H & Y) (8) at the time the patients were examined. All patients were retrospectively collected from clinical records at Okayama University, Kurashiki Heisei, Ota Memorial, and Okayama National Hospitals from 1992 to Information about each patient s age, gender, period from onset to the first hospital visit and neurological findings were collected and compared among PSP, CBD, MSAP and PD groups. Neurological findings included those such as extraocular movility for upper and lateral gazes, optokinetic nystagmus (OKN), postural instability, falls, and the response to LDOPA. Among the abovementioned enrolled patients, neuroimaging studies on MRI were carried out in 55 PSP, 15 CBD, 16 MSAP, and 113 PD patients. The age at examination and period from onset to the first hospital visit of these patients were also calculated and compared. Atrophy of the midbrain tegmentum and frontal lobe in each patient was evaluated in the axial, sagittal and coronal planes on MRI. Myocardial scintigraphy with iodine123 metaiodobenzyl guanidine ( 123 IMIBG) was carried out to investigate cardiac sympathetic function of these patients. All subjects were injected intravenously with 111MBq of 123 IMIBG (Daiichi Radioisotope Laboratories, Tokyo, Japan). Scintigraphic images of the chest were obtained using a doublehead nuclear gamma camera (GCA7200A/DI, Toshiba, Tokyo, Japan) equipped with a mediumenergy, generalpurpose (MEGP) parallelhole collimator. Early and delayed images were obtained 15 minutes and 4 hours after injection, respectively. For the anterior planar image, the dataacquisition matrix was , and a preset time of 5 minutes was used for image acquisition. In planar imaging studies, the hearttomediastinum average count ratio (H/M) was calculated for both early and delayed times, and PD groups were calculated and compared. Ethyl cysteinate dimmersingle photon emission computed tomography (ECDSPECT) was carried out in these patients (55 PSP, 6 CBD, 16 MSAP, and 114 PD patients). The reduction of cerebral blood flow (CBF) in the bilateral area 8 (frontal eye field) (Fig. 1A a, b) was evaluated using the software easy Zscore Imaging System (ezis) version 3.0 (Daiichi Radioisotope Laboratory, Tokyo, Japan), which is useful for the standardized quantitation of CBF. The average of Zscore in the frontal lobe and the largest Zscore in the area 9 (prefrontal area), i.e., the most pronounced CBF reduction (9), was measured. In addition, the largest Zscore in the bilateral area 8, i.e., the most pronounced CBF reduction, was measured, because gaze disturbance may be associated with CBF reduction in this area. And the largest Z score in area 8 was compared separately according to left and right area and by each disease. For statistical analysis, oneway ANOVA was used, and a p value smaller than 0.05 was considered statistically significant. Results The clinical profiles of the patients in each group are summarized in Table 1. The mean age at first hospital visit was about 73 years (y) in PSP group. There was no significant difference in CBD (69 y), PD Yahr 4 (4) (69 y), and PD5 (73 y) groups, whereas the mean age was significantly younger in MSAP (64 y, ** p<0.01), PD1 (61 y, * p< 0.05), PD2 (60 y, * p<0.05), and PD3 (66 y, ** p<0.01) groups compared with PSP group. Sixtyone percent of PSP, 35% of CBD and MSAP, 22% of PD1, 58% of PD2, 35% of PD3, 31% of PD4 and 40% of PD5 patients were men. The mean period from onset to the first visit hospital was about 5.7 y in PSP group. There was no significant difference in PD5 (5.8 y) group, whereas that of CBD (2.7 y), 2776

3 Figure 1. Comparison of easy Zscore Imaging System (ezis) scores among PSP, CBD, MSAP, and PD patients calculated from 99m Tc ethyl cysteinate dimmer single photon emission computed tomography (ECDSPECT). (A) Illustration of the left area 8 (frontal eye field) where the Zscore was measured (a,b). (B) CBF reduction in the left area 8 in PSP patients and no CBF reduction in CBD, MSAP, and PD patients. (C) The largest Zscore of the left (open bars) and right (gray bars) area 8 showed that CBD, MSAP, and PD patients tend to show smaller Zscores (decrease of CBF), but not significantly smaller compared to PSP patients. Calculation of the Zscore of the left area 8 yielded a larger value (CBF reduction) in the PSP than in the PD3 group (* p<0.05), and that of the right area 8, yielded a larger value in the PSP group than in PD3 and PD4 groups (# p<0.05). MSAP (2.3 y), PD1 (2.1 y), and PD2 (3.5 y) groups was shorter (* p<0.05), and that of PD3 (7.6 y) and PD4 (10.2 y) groups was longer (** p<0.01) than that of PSP group. Supranuclear gaze disturbance, either upward or downward gaze limitation, was confirmed in PSP. The averaged upward/ downward gaze angles were 27.7±13.7/ 30.0±13.9 degrees (d) in PSP, and those were all larger (** p<0.01) at 48.2±13.8/ 53.1±12.2 d in CBD, 51.0±10.6/ 55.7±8.9 d in MSAP, 58.9±3.3/ 60.0±0.0 d in PD1, 55.2±9.5/ 57.4±7.7 d in PD2, 49.3±13.7/ 56.4±9.9 d in PD3, 45.1±15.2/ 53.0± 11.6 d in PD4, and 51.6±13.1/ 54.0±13.4 d in PD5. Smooth pursuit, voluntary saccades, and OKN were more severely affected in the PSP group; 80% of PSP patients showed poor or absent OKN elicitation, which was found in only 35% of CBD, 33% of MSAP, 0% of PD1, 13% of PD2, 24% of PD3, 21% of PD4 and 25% of PD5. Almost all patients in PSP (99%), PD3 (96%), PD4 (100%) and PD5 (100%) groups showed postural instability, but falls occurred more frequently in PSP (84%) and PD5 (100%) than in CBD (27%), MSAP (38%) and PD14 (0 63%). PD patients (80100%) showed a better response to LDOPA than PSP (24%), CBD (18%) and MSAP (19%) patients. Among the above patients, % of the patients were examined on brain MRI and radiological study at the first visit; the details are summarized in Table 2. The mean age of the examined patients was 72.3 y in PSP group, and there were no significant differences among the groups, except for a younger patient at 60.5 y in PD2 (** p<0.01). The mean period from onset to the first hospital visit of the examined patients was about 5.3 y in PSP group, and there were no significant differences among all groups, except for 2777

4 Table 1. Background and Clinical Findings in PSP, CBD, MSAP and PD Patients at the First Visit Tauopathy Synucleinopathy Disease PSP CBD MSAP PD (n= 166) Yahr 1 Yahr 2 Yahr 3 Yahr 4 Yahr 5 Number of patients Age 72.6 ± ± ± 7.0** 61.1 ± 10.4* 59.6 ± 13.7** 66.1 ± 11.6** 68.6 ± ± 7.0 Gender M47 F30 M9 F17 M9 F17 M2 F7 M19 F14 M29 F55 M11 F24 M2 F3 Period from onset to the first hospital visit 5.7 ± ± 1.4* 2.3 ± 1.4* 2.1 ± 1.2* 3.5 ± 2.3* 7.6 ± 6.1* 10.2 ± 6.1** 5.8 ± 2.0 Angle( ) Upper gaze 27.7 ± ± 13.8** 51.0 ± 10.6** 58.9 ± 3.3** 55.2 ± 9.5** 49.3 ± 13.7** 45.1 ± 15.2** 51.6 ± 13.1** Lower gaze 30.0 ± ± 12.2** 55.7 ± 8.9** 60.0 ± 0.0** 57.4 ± 7.7** 56.4 ± 9.9** 53.0 ± 11.6** 54.0 ± 13.4** OKN Good Poor Absent 20% 46% 34% 65% 30% 5% 67% 8% 25% 100% 87% 13% 76% 19% 5% 79% 17% 4% 75% 25% Postural instability 99% 31% 77% 0% 9.1% 96% 100% 100% Falls 84% 27% 38% 0% 15% 42% 63% 100% Response to LDOPA 24% 18% 19% 100% 91% 98% 100% 80% * p<0.05 significant difference compared with PSP patients ** p<0.01 significant difference compared with PSP patients Table 2. Comparison of Brain MRI Findings and 123 IMIBG H/M Ratio between PSP, CBD, MSAP and PD Patients Tauopathy Synucleinopathy Disease PSP CBD MSAP PD (n= 113) Yahr 1 Yahr 2 Yahr 3 Yahr 4 Yahr 5 Number of patients Age 72.3 ± ± ± ± ± 13.9** 66.4 ± ± ± 7.1 Period from onset to the first hospital visit 5.3 ± ± ± ± ± ± ± 6.2** 4.0 midbrain Atrophy tegmentum 60% 4% 4% 0% 0% 1% 3% 0% in MRI frontal lobe 55% 64% 4% 0% 6.2% 16% 27% 50% 123 IMIBG H/M ratio Early phase 2.3 ± ± ± ± ± 0.5** 1.7 ± 0.4** 1.7 ± 0.3** 1.7 ± 0.8 Delayed phase 2.3 ± ± ± ± ± 0.7** 1.5 ± 0.4** 1.4 ± 0.4** 1.5 ± 0.6 * p<0.05 significant difference compared with PSP patients ** p<0.01 significant difference compared with PSP patients the longer period of 10.1 y in PD4 (** p<0.01). MRI study showed that atrophy of the midbrain tegmentum was much more frequent in PSP (60%) than in other groups (04%), and atrophy of the frontal lobe was found in 55% of PSP cases, which was similar to 2 groups (CBD 64% and PD5 50%), but less frequent in other groups (MSAP 4%, PD1 0%, PD2 6.2%, PD3 16%, and PD4 27%). In 123 IMIBG myocardial scintigraphy study, the averages of the H/M ratio of PSP, CBD, MSAP, and PD1 groups were not decreased (early/ delayed, PSP 2.3±0.5/ 2.3±0.8: CBD 2.2±0.1/ 2.3± 0.5: MSAP 2.1±0.5/ 2.1±0.6: PD1 2.1±0.6/ 2.1±0.7), while those of PD2, 3, and 4 groups were significantly decreased (** p<0.01) (early/ delayed, PD2 1.8±0.5/ 1.6±0.7: PD3 1.7±0.4/ 1.5±0.4: PD4 1.7±0.3/ 1.4±0.4). There was no significantly difference regarding the average Zscore in the frontal lobe and the largest Zscore of area 9 among PSP and other groups (data not shown); however, in the frontal lobe, CBF reduction was found in bilateral area 8 (frontal eye field) in PSP groups. The largest Z score in bilateral area 8 (frontal eye field) of PSP, CBD, MSAP and PD patients as calculated from ECDSPECT is summarized in Table 3. The examined patients were the same as those in Table 2. As compared to the Zscore in area 8 of the left hemisphere in the PSP group (0.74±1.50), that in PD3 (0.19±1.24) was significantly smaller (* p< 0.05), although that of other groups (CBD 0.29±0.96, MSAP 0.19±1.57, PD1 0.05±1.26, PD2 0.33±1.87, PD ±1.19, and PD5 0.78±2.50) showed a tendency, but 2778

5 Table 3. Comparison of Easy Zscore Imaging System (ezis) Scores between PSP, CBD, MSAP and PD Patients Caluculated from 99m Tc Ethyl Cysteinate Dimmersingle Photon Emission Computed Tomography (ECDSPECT) Tauopathy Synucleinopathy Disease PSP CBD MSAP PD (n=113) Yahr 1 Yahr 2 Yahr 3 Yahr 4 Yahr 5 Number of patients Zscore Lt Area ± ± ± ± ± ± 1.24* 0.29 ± ± 2.50 Rt Area ± ± ± ± ± ± 1.40# 0.51 ± 1.85# 0.84 ± 4.09 *, # p<0.05 significant difference compared with PSP patients not significantly smaller, compared to that of PSP group. As compared to the Zscore in area 8 of right hemisphere in the PSP group (1.84±2.24), that in PD3 (0.68±1.40) and PD4 (0.51±1.85) was significantly smaller (# p<0.05), although that of other groups (MSAP 0.94±1.30, PD1 0.13±1.24, and PD2 1.10±1.56) showed a tendency, but not significantly smaller, compared to that of PSP group. The precise location of left area 8 is shown in Fig. 1A (coronal and sagittal slices in a and b, respectively). The typical ezis score images of ECDSPECT for PSP, CBD, MSAP, and PD patients are shown in Fig. 1B, indicating that the ezis image of the left hemisphere of PSP patients showed severe CBF reduction at frontal and temporal lobes including frontal eye field, but that of CBD, MSAP, and PD patients showed only minimal CBF reduction in the same area (Fig. 1B). The average of the largest Zscore in the area 8 in each hemisphere of PSP, CBD, MSAP and PD patients is shown in Fig. 1C. As compared to the PSP group (0.74±1.50, open bar), the Zscore in area 8 of the left hemisphere in PD3 patients (0.19±1.24) was significantly smaller (* p<0.05), but that of other groups showed a smaller tendency without a significant difference. As compared to the PSP group (1.84±2.24, gray bar), the Zscore in area 8 of the right hemisphere in PD3 (0.68±1.40) and PD 4 (0.51±1.85) patients was significantly smaller (* p<0.05), but that of other groups showed a smaller tendency without a significant difference. The average of the largest Zscore in the right area 8 was larger than that of the left area 8 in almost all groups; it was smaller in only PD1 group, but there were no significant difference between the right and left area 8 in all groups. Discussion Abnormalities of tau and αsynuclein are described in a variety of neurodegenerative diseases. The main tauopathies consist of Alzheimer s disease (AD), PSP, CBD and frontotemporal degeneration (FTDP) with Parkinsonism associated with chromosome 17. On the other hand, the presynaptic protein αsynuclein is a major constituent of Lewytype lesions in PD and in dementia with Lewy bodies (DLB). α synuclein is also found in neuron and glia of MSA including MSAP. This leads to a disease group of synucleinopathies which consists of MSAP and PD. The neuropathological descriptions of these tauopathies and synucleinopathies are rapidly expanding, thus they are sometimes clinically difficult to distinguish. Based on the present analysis, supranuclear gaze disturbance of either upward or downward gaze limitation was confirmed and OKN impairment was more frequently observed in PSP than in the other groups (Table 1). Of interest was that most patients of PSP (99%), PD3 (96%), PD4 (100%), and PD5 (100%) groups showed postural instability, but that only PSP (84%) and PD5 (100%) showed falls of more than 80% compared to the fewer falls in PD3 (50%) and PD4 (63%) groups. Because all PD5 patients were bedridden, PSP patients showed falls more frequently than all other groups under daily walking conditions. The frequency of falls correlates well with vertical extraocular movement (EOM) disturbance (10). PD patients (80100%) showed a much better response to LDOPA than PSP (24%), CBD (18%) and MSAP (19%) patients. As compared with previous reports on PSP, the present results on clinical findings (Table 1) were compatible with previous studies (11 16). Of importance regarding the clinical characteristics of PSP is supranuclear gaze disturbance, OKN impairment and falls at the first visit, while CBD and MSAP show much less frequent supranuclear gaze disturbance, OKN impairment and falls and the same response to LDOPA, and PD shows much less frequent supranuclear gaze disturbance, OKN impairment and falls and a much better response to L DOPA. On brain imaging analysis, midbrain tegmentum atrophy was much more frequently detected in head MRI in PSP (60%) than in all other groups (14%), which may be a characteristic feature of PSP, compatible with previous studies (1719). On the other hand, frontal lobe atrophy was detected in CBD (64%), and PD5 (50%), just the same as in PSP group (Table 2). Functional radiology with 123 IMIBG myocardial scintigraphy did not show a decrease in PSP, CBD, MSAP and PD1 nor a difference among these 4 groups. However, patients of PD2, 3, 4 and 5 showed a significant decrease in 123 IMIBG compared with PSP group. Although a previous report showed that there was no significant difference in the early and delayed H/M ratio among PD patients with a different severity according to the H & Y scale (20), there was no significant decrease in PD1 patients in this study, probably due to the small number of pa 2779

6 tients in PD1. In agreement with another previous studies (21, 22), the present results also support the usefulness of 123 IMIBG myocardial scintigraphy for distinguishing PD 2, 3, 4 and 5 groups from the other 4 groups (Table 2). The Zscore of PD3 group in the left frontal eye field and that of PD3 and PD4 groups in the right frontal eye field were smaller than that of PSP group (Table 3 and Fig. 1C), although that of other groups showed only a tendency without a significant decrease compared to the PSP group. This field, as defined by Brodmann (23) as area 8, is located in the hind part of the medial prefrontal cortex (Fig. 1A). If the function of this area is impaired, eyes cannot be moved voluntarily and vertically (24, 25). CBF reduction in this area should thus reflect or be responsible for the EOM disturbance in PSP. Also in this study, the average of the largest Zscore in right area 8 was larger than that of left area 8 in almost all groups. As a previous report showed that there is an overall increase in the right/left asymmetry about Zscore with age, especially the frontal and temporal neocortex in healthy volunteers (26), it is important to analyze the Zscore on the ipsilateral side. We previously reported that CBF in the frontal lobe, especially in the frontal eye field, is significantly lower in PSP than in pure akinesia, and it is very important for discriminating these similar but possibly different disorders (7). In a previous report, the distinct functional network of brain abnormalities in PSP is the decrease of CBF in cortical and subcortical brain regions (anterior and posterior cingulate cortex: area 24, 32, 23; prefrontal cortex: area 9 and caudate); these are the regions which participate in executive and behavioral functions (9). However, in the present study, there was no significant difference in the average Zscore in the frontal lobe and the largest Zscore in area 9 among PSP and other diseases. The present study is the first report which focused on CBF study on the frontal eye field in PSP, CBD, MSAP and PD. The results obtained here are quite important when considering the mechanism of EOM disturbance in these disorders, and also for differentiation of PSP, CBD, MSAP and PD in an early stage. Supranuclear gaze disturbance of PD3 and PD 4 was much milder (Table 1) and the Zscore of PD3 and PD4 was significantly smaller (Table 3, Fig. 1C) than those of PSP group, even though the mean period from onset to the first visit hospital of PD3 and PD4 groups was longer (Table 1) than that of PSP group. As they showed almost the same frequency of postural instability in PD3 (96%), PD4 (100%) and PSP (99%), it is clearly difficult to differentiate these diseases based on only the clinical symptoms, therefore the Z score of area 8 could be an important supplemental marker to discriminate these diseases along with supranuclear gaze disturbance. The present study showed that PSP, CBD, MSAP and PD are clinically quite distinct based on imaging with MRI and 123 IMIBG myocardial scintigraphy, and ezis analysis of SPECT. These diseases are different from the early stage with EOM disturbance, falls, atrophy of the midbrain tegmentum, and H/M in 123 IMIBG myocardial scintigraphy, and the reduction of CBF in area 8 could serve as a supplemental diagnostic method for distinguishing PSP from PD3 or PD4. The authors state that they have no Conflict of Interest (COI). References 1. Steele JC, Richardson JC, Olszewski J. Progressive supranuclear palsy. Arch Neurol 10: , Rebeiz JJ, Kolodny EH, Richardson EP. Corticodentatonigral degeneration with neuronal achromasia. Arch Neurol 18: 2033, Boeve BF, Lang AE, Litvan I. Corticobasal degeneration and its relationship to progressive supranuclear palsy and frontotemporal dementia. Ann Neurol 54: S15S19, Parkinson J. An Essay on Shaking Palsy. 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