Brain Advance Access originally published online on January 4, 2008
Brain 2008 131(2):438-446; doi:10.1093/brain/awm328
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Effects of disease duration on the clinical features and brain glucose metabolism in patients with mixed type multiple system atrophy
1Department of Neurology, Youngdong Severance Hospital, Yonsei University College of Medicine, Seoul, 2Department of Brain and Bioengineering, KAIST, Daejeon, 3Department of Radiology, Youngdong Severance Hospital, Yonsei University College of Medicine, Seoul, Korea and 4Turku PET Center, University of Turku, Turku, Finland
Correspondence to: Myung Sik Lee, MD, PhD, Professor, Department of Neurology, Youngdong Severance Hospital, 612 Eonjuro, Gangnam-gu, Seoul, Korea E-mail: mslee{at}yuhs.ac
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To study the effect of disease duration on the clinical, neuropsychological and [18F]-deoxyglucose (FDG) PET findings in patients with mixed type multiple system atrophy (MSA), this study included 16 controls and 37 mixed-type MSA patients with a shorter than a 3-year history of cerebellar or parkinsonian symptoms. We classified the patients into three groups according to the duration of parkinsonian or cerebellar symptoms (Group I =
1 year; II = 13–24 months; III = 25–36 months). We performed UPDRS, international cooperative ataxia rating scale (ICARS), and a neuropsychological test battery. We compared the FDG PET findings of each group of patients with controls. Group I patients frequently had memory and frontal executive dysfunction. They showed hypometabolism in the frontal cortex, anterior cerebellar hemisphere and vermis. They had parkinsonian motor deficits, but no basal ganglia hypometabolism. Group II and III patients frequently had multiple domain cognitive impairments, and showed hypometabolism in the frontal and parieto-temporal cortices. Hypometabolism of the bilateral caudate and the left posterolateral putamen was observed in Group II, and whole striatum in Group III. In summary, the cortical hypometabolism begins in the frontal cortex and spreads to the parieto-temporal cortex in MSA. This spreading pattern coincides with the progressive cognitive decline. Early caudate hypometabolism may also contribute to the cognitive impairment. Parkinsonian motor deficits precede putaminal hypometabolism that begins in its posterolateral part. Cerebellar hypometabolism occurs early in the clinical courses and seems to be a relevant metabolic descriptor of cerebellar deficits.
Key Words: multiple system atrophy; cognitive impairment; positron emission tomography
Abbreviations: COWAT, controlled oral word association test; FDG, [18F]-deoxyglucose; FWHM, full-width half-maximum; GCI, glial cytoplasmic inclusion; ICARS, international cooperative ataxia rating scale; IQR, interquartile range; K-BNT, Korean version of the Boston naming test; MSA, multiple system atrophy; PET, positron emission tomography; RCFT, Rey–Osterrieth complex figure test; SVLT, Seoul verbal learning test; TE, echo time; TR, repetition time; UPDRS, unified Parkinson's disease rating scale.
Received September 10, 2007. Revised November 8, 2007. Accepted December 11, 2007.
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Introduction |
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Patients with multiple system atrophy (MSA) usually present with a variable mixture of parkinsonian, cerebellar, pyramidal and autonomic symptoms and signs (Wenning et al., 1997
). Pathological studies of MSA show degeneration of the substantia nigra, striatum, pallidum, cerebellum, pontine nuclei, inferior olivary nucleus, pyramidal tract and intermediolateral cell column of the spinal cord. In addition to neuronal loss and gliosis, glial and neuronal inclusion bodies occur in cerebral white matter and cortices, as well as the striatonigral and olivopontocerebellar systems (Papp et al., 1989; Papp and Lantos, 1994). However, post-mortem pathological findings usually represent the end result, but not the early evolution of the disease.
In vivo examinations of MSA patients with positron emission tomography (PET) and single photon emission computed tomography studies have shown hypometabolism and hypoperfusion in the frontal cortex, striatum, cerebellum and brainstem (De Volder et al., 1989; Eidelberg et al., 1993; Perani et al., 1995; Antonini et al., 1997; Taniwaki et al., 2002; Juh et al., 2004; Cilia et al., 2005; Matsui et al., 2005). However, most studies showed a sum of neuronal functional changes in a small number of patients without controlling for age, age at the onset of disease, duration of disease and severity of clinical deficits.
Duration of the disease is an important factor that would influence topographical distribution and severity of pathological changes of neurodegenerative diseases (Apaydin et al., 2002). To understand the pattern of evolution of pathological changes, we investigated the effect of disease duration on the findings of [18F]-deoxyglucose (FDG) PET studies in patients with early MSA.
Patients
From July 2004 to May 2007, 75 MSA patients, who fulfilled consensus criteria for possible or probable MSA (Gilman et al., 1999), were admitted to Youngdong Severance Hospital, Yonsei University, Seoul, Korea. Of these, 55 patients were recruited with a shorter than a 3-year history of parkinsonian or cerebellar symptoms, regardless of the duration of autonomic symptoms. Of the 55 patients, 36 patients had probable MSA and the remaining 19 patients had possible MSA. During the follow-up period (mean = 12.9 months), twelve of 19 patients with possible MSA developed autonomic dysfunction sufficient for the diagnosis of probable MSA. Of the 48 probable MSA patients, we excluded three patients with pure cerebellar type MSA and five patients with pure parkinsonian type MSA to include rather homogeneous patients. We also excluded three patients with the Korean version of Mini Mental State Examination (K-MMSE) score lower than 24. Among the 37 patients with mixed type MSA, 19 patients (predominated by parkinsonism = 11, predominated by cerebellar deficits = 8) were receiving a single levodopa treatment (mean daily dose = 739.5 mg) or a combination with selegilline (daily dose = 5 mg).
Thus, this study included 37 patients with mixed type MSA and 16 age-matched healthy controls [median age = 61.0 years, interquartile range (IQR) = 58.0–64.3 years, 5 males and 11 females]. According to the duration of parkinsonian or cerebellar symptoms, patients were classified into three groups (Group I = duration 1 year or shorter; Group II = duration between 13 and 24 months; Group III = duration between 25 and 36 months). In all subjects, PET studies were performed after written informed consents.
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Methods |
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Evaluation of parkinsonian and cerebellar deficits
We measured the unified Parkinson's disease rating scale (UPDRS) motor score to assess the degree of parkinsonian deficits and the international cooperative ataxia rating scale (ICARS) scores to evaluate the severity of cerebellar deficits (Trouillas et al., 1997
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Evaluation of cognitive function
Thirty-five of the 37 patients underwent a standardized neuropsychological test battery (Seoul Neuropsychological Screening Battery) (Kang and Na, 2003). The battery consists of various tests evaluating attention, language, praxis, four elements of Gerstmann syndrome, visuoconstructional function, verbal and visual memory, and frontal executive functions. Among them, numerical tests were digit span test (forward and backward), Korean version of the Boston Naming Test (K-BNT) (Kim and Na, 1999), Rey–Osterrieth Complex Figure Test (RCFT; copying, immediate and 20-min delayed recall and recognition), Seoul Verbal Learning Test (SVLT; three learning-free recall trials of 12 words, 20-min delayed recall trial for these 12 items and a recognition test), phonemic and semantic Controlled Oral Word Association Test (COWAT) and Stroop Test (word and colour reading of 112 items during a 2-min period). Age-, sex-, and education-specific norms for each test based on 447 healthy subjects were available.
We classified the cognitive function domain into four categories; memory, language, visuospatial function and frontal executive function and the pattern of cognitive dysfunction as single domain or multiple domain impairments. Memory function was evaluated with the delayed recall on the SVLT or the RCFT, language function with K-BNT and visuospatial function with copying score of the RCFT. The results of these numerical cognitive tests were considered as abnormal when the scores were below the 16th percentiles of the norms for the age-, sex- and education-matched controls (Kang and Na, 2003). The patients were considered to have frontal executive dysfunction if they showed impairment in at least two of the following three tests: motor executive function tests (contrasting programme, Go/no-go, fist-edge-palm, alternating hand movement, alternative square and triangle drawing and Luria loop), the COWAT and the Stroop Test.
Brain FDG PET studies
Acquisition of FDG PET scan images
After overnight fasting and withdrawal of all anti-parkinsonian medications, FDG PET study was performed in a quiet and dimly lit room with the subjects’ eyes open. After injecting 5.18 MBq/kg of FDG into the antecubital vein, radial arterial blood was sampled nine times at 5 to 10-s intervals for 1 min and then sampled 15 times at 30 s to 10 min of progressively increasing intervals. The [18F]-radioactivity curve was obtained for quantification. Using an Allegro PET scanner (Philips Medical Systems; gadolinium oxyorthosilicate crystals), PET scanning was performed at 45–55 min after injecting FDG. After 1.5 min of transmission, 17 min of emission and a final 1.5 min of transmission scans, three-dimensional (3D) PET image was reconstructed by 3D-RAMLA (3D version of the row action maximum likelihood algorithm).
Brain magnetic resonance imaging (MRI) studies
On the day of PET scan studies, brain MRI studies were performed using 3D spoiled gradient-recalled (3D-SPGR) sequences on 3.0 Tesla MR scanner (Signa EXCITE, GE Medical Systems, Milwaukee, WI). We obtained 160 slices of axial T1-weighted images with a repetition time (TR) of 6.8 ms, a minimum of echo time (TE) between 1.6 and 11.0 ms, a prep time of 300 msec, a flip angle of 20°, a matrix of 256 x 256 and a slice thickness of 1 mm. The resulting 3D-MR image was reformatted parallel to the anterior and posterior commissures (AC-PC) line and centred at the midpoint of AC-PC line. Finally, the image was resampled with a voxel size of 1 x 1 x 1 mm for normalization. We also obtained 32 slices of axial T2-weighted images (TR = 5,250 ms, TE = 120 ms, flip angle = 90°, matrix = 512 x 512 and slice thickness = 5 mm).
Pre-processing of PET and MR images
Individual MR images were used for spatial normalization of the FDG PET image. Normalization was performed automatically with the PFUS module in the software PMOD version 2.75 (PMOD technologies Ltd., Zurich, Switzerland). The subject's FDG PET image was co-registered to individual MR image. Using affine transformation and 12 non-linear iteration by 7 x 8 x 7 basis function, the MR image was transformed to MNI-152 (Montreal Neurological Institute) T1-weighted MRI template. During this step, the individual transformation matrix was obtained and applied to the co-registered FDG PET image. Finally, a spatially normalized FDG PET image was obtained. The fitness of normalized PET and MR images was verified visually in each normalization step.
The parametric PET image was generated by the PMOD with FDG-autoradiography method (lump constant = 0.437, k1 = 0.102, k2 = 0.130, k3 = 0.062, k4 = 0.0068) (Huang et al., 1980). Subsequently, an isotropic Gaussian kernel of 12 mm full-width half-maximum (FWHM) was applied to the parametric PET image to improve the signal-to-noise ratio. Finally, this normalized and smoothed parametric PET image was used for statistical analysis.
Statistical parametric mapping
Using the group comparison model covariated with age in SPM2 (Statistical Parametric Mapping; Wellcome Department of Cognitive Neurology, London, UK) implemented to MATLAB 7.0 (MathWorks, Natick, MA), we compared the cerebral glucose metabolism of each subgroup of MSA patients with the controls. A family wise error (FWE)-corrected P-value <0.05 was considered statistically significant.
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Results |
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Characteristics and clinical features of patients (Table 1)
Of the 37 patients with mixed type MSA (22 men and 15 women), 17 patients had predominantly parkinsonian features (MSA-P) and the other 20 patients predominantly cerebellar deficits (MSA-C). There were 13 patients in Group I (MSA-P = 4, MSA-C = 9), 12 patients in Group II (MSA-P = 6, MSA-C = 6) and 12 patients in Group III (MSA-P = 7, MSA-C = 5).
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The ages of the patients (median age = 61.0 years, IQR = 55.0–64.5 years) and controls were not different (Mann–Whitney Test, P > 0.05). In addition, the ages of the three groups of MSA patients [median (IQR) age: Group I = 58.0 (51.0–65.0), Group II = 60.5 (49.8–69.0), Group III = 61.0 (57.8–64.5) years] and controls were not significantly different (Kruskal–Wallis Test, P = 0.851). The post hoc comparison between each group and controls also did not show difference (Mann–Whitney Test, P > 0.05). The median (IQR) age of disease onset was 59.0 (53.5–62.5) years. The median (IQR) of disease duration was 15.0 (12.0–27.0) months [Group I = 8.0 (7.0–12.0) months, Group II = 15.5 (14.0–21.0) months, Group III = 32.0 (27.0–34.5) months].
The median (IQR) UPDRS motor score was 23.0 (19.0–33.5) and the median (IQR) ICARS score was 23.0 (18.0–34.5). There was significant difference in the UPDRS motor scores among the three groups (Kruskal–Wallis Test, P = 0.037). However, the ICARS scores were not significantly different among the three groups (Kruskal–Wallis Test, P = 0.164).
Cognitive dysfunction (Table 2)
The median (IQR) K-MMSE score of the 37 patients was 29.0 (27.5–30.0). No patient satisfied the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria for dementia.
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Among 35 patients who underwent neuropsychological tests, only six (17.1%) showed a normal cognitive function in all four domains tested (memory, frontal, visuospatial and language functions). Four of them were in Group I, and the remaining two were in Group II and III. Twenty-nine patients (82.9%) had impairments in at least one cognitive domain. Twenty-three patients (65.7%) had memory impairment, 17 (48.6%) had frontal dysfunction, nine (25.7%) had visuospatial dysfunction and two (5.7) had language dysfunction. Fourteen of the 35 patients (40.0%) had an impairment in a single domain (either memory, frontal, visuospatial or language dysfunction). Fifteen patients (42.9%) had impairments in at least two domains. The individuals with multiple domain impairments were found more frequently in Group III (six patients, 60.0%) than in Group I (four patients, 30.8%) and Group II (five patients, 41.7%).
T2-weighted brain MRI findings (Table 3)
Of the 37 patients with MSA, 34 patients had cerebellar cortical atrophy and 23 patients had hot cross bun sign in the pons. They were frequently found even in Group I patients. About one-third of the patients showed more than moderate degree of atrophy of the posterior putamen. The putaminal rim sign (high signal intensity lines lateral to the putamen) was observed in 13 of the 37 patients. It was found in patients with duration longer than 12 months.
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PET findings (Table 4, Figs 1 and 2)
Patients in Group I showed decreased glucose metabolism in the right lateral and medial frontal cortex (Brodmann area; BA6, 8, 9, 45 and 47), left lateral and medial frontal cortex (BA6, 8, 9, 44 and 45), cerebellar vermis and bilateral anterior cerebellar hemispheres. Group II patients showed hypometabolism in the right lateral frontal cortex (BA4, 6, 8, 9, 10, 45 and 47), left lateral and medial frontal cortex (BA4, 6, 8, 9, 10, 11, 45, 46 and 47), right superior, middle and inferior temporal cortex (BA20, 21, 22 and 42), left superior, middle and inferior temporal cortex (BA21, 37, 39 and 42), left fusiform gyrus (BA20 and 37), right post-central gyrus (BA3, 1 and 2), left angular gyrus (BA39), left precuneus (BA19) and right posterior cingulate cortex (BA31). There were also hypometabolic areas involving bilateral caudate nucleus and left posterolateral putamen. Also, the cerebellar vermis and bilateral cerebellar hemispheres were involved. Comparing to the Group II patients, the basal ganglia hypometabolic area in the Group III patients spread anteromedially to involve the entire putamen and globus pallidus.
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Discussion |
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Cerebral cortical dysfunction in early MSA
FDG PET studies of MSA patients have reported normal or reduced cerebral cortical glucose metabolism (De Volder et al., 1989
; Kume et al., 1992; Perani et al., 1995; Taniwaki et al., 2002; Juh et al., 2004; Juh et al., 2005). However, MSA patients with shorter than a 3-year history of cerebellar or parkinsonian symptoms may show glucose hypometabolism in the primary motor, premotor and pre-frontal cortices (De Volder et al., 1989; Otsuka et al., 1996).
In the present study, MSA patients with disease duration shorter than 1 year showed frontal hypometabolism, and patients with disease durations longer than a year showed hypometabolism in more widespread cerebral cortical areas involving the frontal, temporal, parietal and cingulate cortices. In contrast to patients with Parkinson's disease, the parieto-temporal association and occipital cortices were preserved (Eidelberg et al., 1994; Hu et al., 2000). The partial volume effect of the grey matter atrophy can affect the glucose metabolism studied with the brain FDG PET scan. However, in accordance with previous studies (Brenneis et al., 2003, 2006), voxel-based morphometry of the MR images of the patients included in this study showed atrophy of the perisylvian and orbitofrontal cortical areas. Therefore, cortical atrophy is unlikely to play a major role in the cerebral cortical hypometabolism found in the present study.
In pathological studies of MSA, cerebral cortical changes have not received much attention and inconsistent results on neuronal loss and gliosis of the cerebral cortex have been reported. Some pathological studies showed mild to moderate neuronal loss and adjacent white matter changes in the superior and middle frontal gyri, supplementary motor area, precentral gyrus, postcentral gyrus and inferior parietal lobule (Spargo et al., 1996; Wakabayashi et al., 1998; Konagaya et al., 1999; Tsuchiya et al., 2000; Su et al., 2001). Neuronal loss and astrocytosis in the layer V of the precentral gyrus was found, even in MSA patients with the disease duration shorter than 3 years (Tsuchiya et al., 2000; Su et al., 2001). However, a review of 203 pathologically proven MSA patients reported that about 78.4% of the patients had no abnormalities in the cerebral cortex, and only 8.9% had moderate to severe abnormalities (Wenning et al., 1997).
Glial cytoplasmic inclusions (GCIs) were found in the frontal lobe, particularly in the supplementary motor, cingulate, primary motor and premotor cortices (Papp and Lantos, 1994). The distribution pattern of cerebral cortical GCI is similar to that of cortical neuronal loss (Papp et al., 1989; Papp and Lantos, 1994; Inoue et al., 1997; Su et al., 2001). GCI is known to precede neuronal loss and gliosis (Wenning et al., 1994; Inoue et al., 1997; Wenning and Jellinger, 2005). Indeed, a patient who died 15 months after the onset of cerebellar type MSA had GCIs in the precentral gyrus (Wakabayashi et al., 2005).
We postulate that the early widespread cortical glucose hypometabolism observed in the present study is more likely caused by cortical GCI than by cortical neuronal loss. Another possible explanation may be damage to the afferent cortical inputs arising from the subcortical nuclei (e.g. locus ceruleus and substantia nigra) (Papp et al., 1989; Wenning et al., 1994).
Previous studies on cognitive changes in patients with MSA consistently reported frontal executive dysfunction (Robbins et al., 1992, 1994; Monza et al., 1998; Berent et al., 2002; Bak et al., 2005; Paviour et al., 2005; Bürk et al., 2006). Accordingly, the present study showed that about half of the MSA patients develop frontal dysfunction within a year after the onset of cerebellar or parkinsonian symptoms. These findings coincide with our FDG PET results showing early medial and lateral frontal glucose hypometabolism.
A previous study reported that about 40% of MSA patients have memory impairment (Bak et al., 2005). In the present study, 8 (22.9%) of 35 patients had a single amnestic and 15 (42.9%) had multiple amnestic cognitive impairments. The early memory impairment in patients with MSA can be attributed to the hypometabolism of the prefrontal and inferior frontal cortex (Tulving et al., 1994; Buckner and Koutstaal, 1998; Buckner et al., 1999). The proportion of patients with multiple amnestic cognitive impairments was 30.8% in Group I, and it increased up to 60% in Group III.
Only a small proportion of patients with MSA are known to have visuospatial dysfunction (Bak et al., 2005, 2006; Bürk et al., 2006). However, a longitudinal study showed progressive deterioration of visuospatial function in MSA (Soliveri et al., 2000). In the present study, no one had a single visuospatial function domain impairment. However, as the duration of disease increased, the proportion of patients who had visuospatial dysfunction as a component of their multiple domain impairments increased up to 40%. This is in accordance with the spread of frontal hypometabolism to involve parieto-temporal areas.
Language impairment has rarely been reported in patients with MSA (Robbins et al., 1992; Bak et al., 2005). Two (5.7%) of our patients had language impairment. Our FDG PET studies showed preserved cortical motor and sensory language areas, except left angular gyrus involvement in Group II patients.
Basal ganglia dysfunction in early MSA
Although post-mortem pathological studies of MSA have consistently reported damage to the basal ganglia, its evolution from early disease to the final outcome of neurodegeneration found at autopsy is largely unknown (Fearnley and Lees, 1990; Wenning et al., 1995; Ozawa et al., 2004; Jellinger et al., 2005). In previous literatures, we identified post-mortem pathological findings of 10 MSA patients who died within 3 years after the onset (Papp et al., 1989; Fearnley and Lees, 1990; Kume et al., 1993; Su et al., 2001; Wakabayashi et al., 2005). Except one patient with pure olivopontocerebellar pathology (Wakabayashi et al., 2005), the others had variable degree neuronal loss in the putamen, caudate and substantia nigra.
Although our Group I patients had parkinsonian motor deficits ranging from 9 to 38 on UPDRS motor score, they showed no striatal hypometabolism. In MSA, calcineurin positive medium spiny striatal neurons are depleted severely in the dorsolateral part of the posterior putamen, but choline acetyltransferase positive striatal neurons are preserved (Sato et al., 2007). The nigrostriatal dopaminergic terminals comprise less than one-fifth of the striatal synapses (Tennyson et al., 1974; Pickel et al., 1981). Therefore, in early MSA, the additive effect of selective striatal neuronal loss and partial damage to the nigrostriatal neurons may cause parkinsonian deficits, but too small changes in striatal synaptic activity to be detected by FDG PET studies. A multi-tracer PET study of the nine MSA patients also showed no correlation between the degree of putaminal FDG uptake and the severity of parkinsonian motor deficits (Antonini et al., 1997). Another possible explanation may be non-specific contamination of UPDRS motor scores by cerebellar motor slowing (Tison et al., 2002).
In our study, as expected, Group II and III patients had more severe parkinsonian motor deficits than Group I patients. In Group II, glucose metabolism was reduced in the caudate nucleus and posterolateral putamen. It is interesting to note the early involvement of the posterolateral putamen, where the somatic motor inputs from the cerebral cortex and the nigrostriatal dopaminergic terminals are connected (Hedreen and DeLong, 1991). The caudate receives afferent fibres mainly from the prefrontal cortex (Hedreen and DeLong, 1991; Lehericy et al., 2004). Therefore, dysfunction of the caudate may contribute to frontal executive dysfunction observed in our patients (Alexander and Crutcher, 1990).
In Group III, the basal ganglia hypometabolic area extended to involve whole putamen and globus pallidus. Such changes may be caused by reduced activities of afferent inputs to the pallidum and striatum, as well as loss of striatal and pallidal intrinsic neurons (Papp et al., 1989).
Cerebellar dysfunction in early MSA
In MSA, there is neuronal loss in the pontine nuclei, inferior olivary nucleus, cerebellar hemisphere and cerebellar vermis (Papp and Lantos, 1994; Wenning et al., 1996; Jellinger et al., 2005). There is a deposition of many GCIs and extensive myelin loss in the cerebellar white matter, middle cerebellar peduncle and basis pontis (Papp et al., 1989; Papp and Lantos, 1994; Inoue et al., 1997; Tsuchiya et al., 1998; Su et al., 2001; Wakabayashi et al., 2005). Such changes are remarkable even in the early stage of the disease, when the loss of Purkinje cells in the cerebellar cortex is not evident or mild (Papp et al., 1989; Inoue et al., 1997; Su et al., 2001; Wakabayashi et al., 2005).
In the present study, the cerebellar vermis and the anterior cerebellar hemisphere were involved within 1 year after the onset of parkinsonian or cerebellar symptoms. These findings are in accordance with pathological studies that have shown predominant involvement of anterior cerebellar hemisphere (Kume et al., 1991; Wenning et al., 1996).
In summary, this is the first in vivo FDG PET study showing a pattern of progression of metabolic changes in the brains of mixed type MSA patients. However, community-based longitudinal FDG PET studies are needed to verify the results of the present study.
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Acknowledgements |
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J.O.R. was supported by clinical grants of Turku University Hospital, by the Academy of Finland and by the Sigrid Juselius Foundation.
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