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PubMed2005

The North American Multiple System Atrophy Study Group.

The North American Multiple System Atrophy Study Group involves investigators in 12 US medical centers funded by a grant from the National Institutes of Health. The objectives are to examine the environmental and genetic risk factors for MSA; elucidate pathogenic mechanisms underlying the disorder; and refine evaluations used for assessment. During its first year, the group enrolled 87 patients, implemented four cores, and initiated four scientific projects. Most patients among the 87 had parkinsonian features, which frequently began asymmetrically and remained asymmetrical; one-third responded to levodopa and many developed levodopa complications; almost two-thirds of the patients had cerebellar dysfunction, of these 90% had ataxia; urinary incontinence occurred commonly, and sleep disorders affected most. The investigators studied the effects of oxidative and nitrative stress upon the formation of alpha-synuclein inclusions; generated transgenic models of alpha-synuclein accumulation that recapitulate several behavioral and neuropathological features of MSA; and compared the severity of the autonomic features of MSA, Parkinson's disease and dementia with Lewy bodies.

Animals↗
PubMed1997

Cerebellar presentation of multiple system atrophy.

Early diagnosis of multiple-system atrophy (MSA) is important in patients presenting with late-onset cerebellar ataxia because it has a less favourable prognosis than other degenerative ataxic disorders. We report cerebellar presentation of MSA in a series of 16 patients, 3 of whom later developed parkinsonism. Two-thirds of them had early evidence of impaired postural reflexes with a history of recurrent falls. Some of these had a narrow-based, unsteady gait, unlike the more classic broad-based gait ataxia of cerebellar disease. On review of the patients' histories, genitourinary dysfunction (particularly impotence) was present at the onset of, or preceding, cerebellar ataxia in 60% of patients, but this had often been attributed to age, or to urological or gynaecological causes. External striated anal or urethral sphincter electromyography (EMG) demonstrated features of chronic denervation and reinnervation in 14 (93%) of 15 patients, consistent with degeneration in Onuf's nucleus as occurs in MSA. Autonomic function tests were abnormal in 9 (64%) of 14 patients. Our data suggest that close enquiry into genitourinary function and analysis of the gait disorder can be useful pointers to a diagnosis of MSA in patients with an unexplained adult-onset progressive cerebellar syndrome, and that sphincter EMG is the most useful investigation in this context.

Adult↗
PubMed1986

Tobacco intolerance in multiple system atrophy.

In a patient with multiple system atrophy, the ataxia was temporarily exacerbated by cigarette smoking. The phenomenon is attributed to a direct effect of nicotine on the central nervous system, rather than being secondary to autonomic changes. Its prevalence and specificity are currently unknown.

Autonomic Nervous System Diseases↗
PubMed2003

Increased myocardial uptake of iodine-123 metaiodobenzylguanidine on delayed images, compared with early images, in patients with multiple system atrophy.

We present 2 interesting cases of multiple system atrophy in which increased myocardial iodine-123 metaiodobenzylguanidine uptake was observed on delayed images (3 hours after injection) compared with early images (15 minutes after injection). These findings have not been previously described. The duration of symptoms was less than 1 year in both these patients. The mechanism responsible for these findings is not clearly understood, but could be related to the pathophysiological changes in the early stage of multiple systemic atrophy.

3-Iodobenzylguanidine↗
PubMed2006

Cortical atrophy in the cerebellar variant of multiple system atrophy: a voxel-based morphometry study.

This study aimed to determine in vivo the atrophy patterns in clinically established cerebellar variant of multiple-system atrophy (MSA-C) using voxel-based morphometry (VBM). Thirteen patients with MSA-C (12 probable, 1 possible) and 13 healthy controls matched for age and sex were included. High-resolution MR images were acquired with a 1.5 T scanner. Images were normalized onto a study-specific template, segmented into the tissue compartments, modulated with the Jacobian determinants, and finally smoothed with a Gaussian kernel filter of 10 mm. The general linear model was used to assess statistical differences in gray and white matter. Infratentorial atrophy was observed in the cerebellar hemispheres, vermis, mesencephalon, and pons of MSA-C patients. Supratentorial volume loss was found in orbitofrontal and mid-frontal regions as well as in temporomesial and insular areas of both hemispheres. A negative correlation was observed between a cerebellar ataxia score and the volume of cerebellar hemispheres, peduncles, and pons. To compare this atrophy pattern to that of spinocerebellar ataxia (SCA2), which was previously reported by our group, a conjunction analysis was assessed. We observed a volume loss shared by both disorders comprising the cerebellum, vermis, pons, mesencephalon, orbitofrontal, mid-frontal, and temporomesial cortex of both hemispheres as well as the left insular cortex.

Adult↗
PubMed1999

[Striatonigral degeneration and sporadic olivopontocerebellar atrophy: a consideration of the clinical entity of multiple system atrophy].

Striatonigral degeneration (SND) and sporadic olivopontocerebellar atrophy (sOPCA) are categorized under multiple system atrophy (MSA), since these disorders have common clinical and pathological features. However, it is still uncertain whether these disorders are manifestation of the same disease. In this study, we performed both clinical and neuroradiological studies on patients with SND or sOPCA in whom clinical diagnosis was based on a criteria during eight years in our hospital. A total of forty patients had SND and thirty-one patients had sOPCA. The onset ages of patients with SND (60.7 +/- 8.7, mean +/- SD) were significantly higher than those with sOPCA (55.4 +/- 7.9). In both SND and sOPCA patients, about 20% had clinical symptoms suggesting the involvement of multiple systems: pyramidal, cerebellar, extrapyramidal and autonomic symptoms. In 55% of the SND patients, cerebellar symptoms could be observed, and the same percentage of sOPCA patients had parkinsonism. Although, as defined, cerebellar symptoms were predominant in sOPCA patients and parkinsonism was predominant in SND patients, the SND patient group was particularly homogeneous with respect to clinical characteristics. The initial symptoms of SND were parkinsonian gait or tremors. Almost all patients exhibited asymmetrical appearance of the parkinsonian symptoms, such as rigidity, tremors, and bradykinesia. Tremors at rest were observed in two-thirds of the patients with SND during the course of their illness, but dementia was infrequently observed. There was no detectable limitation in horizontal eye movements in patients with SND. The progression of the disability of patients with SND was rapid; according to the clinical rating scale of parkinsonism, the average level of disability deteriorated to Hoehn-Yahr's stage III after three years from disease onset, and then deteriorated to stage IV after four years. Neuroradiologically, only a small proportion of patients with SND (27%) showed magnetic resonance image (MRI) findings suggesting OPCA pathology, such as volume loss in the brainstem or cerebellum with/without T2-high signaling of transverse fibers of pons or T2-high signaling of the middle cerebellar peduncle. Simultaneously, a small proportion of the patients with sOPCA (20%) showed MRI findings suggesting putaminal pathology, such as T2-low intensity signals of the putamen with linear T2-high intensity signals around the lateral putamen. Our results suggest that SND and sOPCA can be clearly differentiated, at least from clinical or neuroradiological aspects. Since there is still no evidence indicating that each disorder is a clinical variant of a single disease caused by the same etiology, a differentiation might be important for future pathogenetical studies.

Adult↗
PubMed2006

Transcriptional changes in multiple system atrophy and Parkinson's disease putamen.

Multiple system atrophy (MSA) and sporadic, non-mendelian Parkinson's disease (PD) are progressive neurodegenerative disorders with overlapping clinical symptoms and pathology. The etiology of both disorders is unknown, and complex combinations of multiple susceptibility genes and environmental factors are thought to be involved. Both disorders are characterized by ubiquitous alpha-synuclein aggregates in distinct regions and cell types of the central nervous system. In PD, alpha-synuclein-positive aggregates appear to be largely neuronal while in MSA oligodendroglial inclusions prevail. In PD patients, the alpha-synuclein pathology is thought to evolve in a rather regular pattern, starting in the brainstem and olfactory bulb and extending gradually onto the substantia nigra and ultimately the cerebral cortex while the cerebellum is largely spared. MSA pathology has not been graded in a similar way yet; neuropathological analyses revealed neurodegeneration and gliosis primarily in the brainstem, midbrain and basal ganglia and the cerebellum, while the cortex is largely spared. To identify disease-specific transcriptional patterns in MSA, we chose CNS regions differentially affected in MSA and PD for comparative gene expression profiling: putamen, cerebellum and occipital cortex. Four genes were regulated in both MSA and PD putamen and twelve in MSA and PD cerebellum. Regulated transcripts were validated using real-time quantitative RT-PCR, and immunohistochemistry was performed for the most significantly downregulated transcripts in MSA and PD putamen, GPR86 and RGS14, associated with G protein signaling and transcriptional regulation.

Aged↗
PubMed2006

The "cross" signs in patients with multiple system atrophy: a quantitative study.

Patients with multiple system atrophy (MSA) may show the "cross" sign in the pontine base that has been considered as an expression of the degeneration of pontine neurons and transverse pontocerebellar fibers. However, correlations between pontine base atrophy and existence of "cross" sign have not been fully investigated. The authors studied 68 patients with MSA (47 MSA-C [predominantly cerebellar ataxia], 21 MSA-P [predominantly parkinsonism], mean [+/-SD ] 58.7 +/- 10.9 years). T1-weighted (T1W) sagittal and axial images and T2-weighted (T2W) axial images were obtained for all patients and controls. To measure the areas of pontine basis and cerebellar vermis, the authors used midsagittal T1W images and analyzed a bit map transformed on a computer. They classified atrophy in the pontine base into 3 grades. There is significant correlation between atrophies of pontine base and existence of the cross sign. All patients with a smaller area of pontine base 2 standard deviations below those of normal controls had the cross sign. This supports that existence of the cross sign depends only on the extent of pontine base atrophies.

Adult↗
PubMed1992

Accumulation of tubular structures in oligodendroglial and neuronal cells as the basic alteration in multiple system atrophy.

In 8 brains of patients with various combinations of striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome, inclusion bodies were demonstrated in the cytoplasm and nucleus of both neuronal and oligodendroglial cells and in neuronal processes by means of silver staining, immunocytochemistry and electron microscopy. Differing from oligodendroglial cytoplasmic inclusions recognized by anti-ubiquitin, anti-alpha- and anti-beta-tubulin, and anti-tau antibodies, neuronal cytoplasmic inclusions were stained only by anti-ubiquitin antibody but not with those raised against cytoskeletal proteins. Tubular structures forming the inclusion bodies irrespective of their glial or neuronal location, have fuzzy cover and side extensions which make them similar to the linear structures described in motor neuron diseases. Our study proves that the accumulation of abnormal tubular structures in both oligodendrocytes and neurons is the basic pathological alteration in multiple system atrophy and defines multiple system atrophy as a group of diseases with similar cellular pathology or as a nosological entity.

Atrophy↗
PubMed2006

alpha-synuclein from platelets is not phosphorylated at serine 129 in Parkinson's disease and multiple system atrophy.

Parkinson's disease (PD) and multiple system atrophy (MSA) are characterized pathologically by inclusions in the brain containing alpha-synuclein, which is phosphorylated at serine 129. alpha-Synuclein is present not only in the brain but also in platelets; platelets have previously been used to study mitochondrial function in PD. We undertook to determine whether alpha-synuclein extracted from platelets of patients with PD and MSA is phosphorylated at serine 129 and could be used as a peripheral marker of these disorders. Immunoblots indicated that platelet alpha-synuclein is not phosphorylated at serine 129 in PD and MSA.

Adult↗
PubMed2005

Grading of neuropathology in multiple system atrophy: proposal for a novel scale.

Multiple system atrophy (MSA), a sporadic progressive synucleinopathy of advanced age, is separated into two clinic opathological subtypes: MSA-P (striatonigral degeneration [SND]) with predominant parkinsonian features and MSA-C (olivopontocerebellar atrophy [OPCA]) with predominant cerebellar ataxia. We propose a novel morphological grading system for both subtypes to compare lesion intensities and their possible clinical validity. Forty-two autopsy cases of MSA were separated into four grades (SND 0-III and OPCA 0-III) based on semiquantitative assessment of neuronal loss, astrogliosis, and presence of alpha-synuclein-positive glial cytoplasmic inclusions (GCI) in striatum, globus pallidus, substantia nigra, pontine basis, cerebellum, and inferior olives. Whereas a recent grading system restricted to SND reflected disease progression and dopa-responsiveness, there was considerable variation in the morphological combination between SND and OPCA, with only around half the cases with OPCA II (moderate) and III (severe) showing comparable grades of both types, whereas OPCA 0 and I (no or little degeneration) was combined with all grades of SND. Twenty-two cases showing OPCA 0 + SND II (n = 3), OPCA I + SND I-II (n = 11), and OPCA I + SND III (n = 8) were classified as pure or predominant SND, consistent with MSA-P. Twenty cases showing OPCA II + SND II/III (n = 7) and OPCA III + SND III (n = 13) were classified as predominant OPCA, consistent with MSA-C. In MSA-P, the mean age of onset was higher than it was in MSA-C (55.1 vs. 50.5 years), but the mean duration of illness was shorter in MSA-P (5.3 vs. 6.7 years). Presenting symptoms in MSA-P were mainly parkinsonism, whereas in MSA-C they were mainly gait disorders (14 vs. 1; P < 0.001). Among clinical key symptoms, parkinsonism was more frequent than were cerebellar signs in MSA-P; in MSA-C it was the reverse (P < 0.01), whereas other symptoms (autonomic/urinary failure) showed no differences. Parkinsonism was infrequent in MSA-C even when OPCA was associated with SND, suggesting a masking effect by cerebellar system involvement. High terminal Hoehn and Yahr stages were more frequent in MSA-P (P < 0.01), some with good-to-moderate initial levodopa (L-dopa) response. Although the proposed morphological grading of both MSA-P and -C correlates well with initial symptoms and clinical key features of both types, further prospective studies are required to validate the clinical utility of the proposed MSA grading scales for future intervention studies.

Cerebellar Ataxia↗
PubMed2003

In vivo voxel-based morphometry in multiple system atrophy of the cerebellar type.

BACKGROUND: Multiple system atrophy (MSA) is a sporadic neurodegenerative disease. According to the clinical presentation a parkinsonian type and a cerebellar type (MSA-C) are distinguished. OBJECTIVE: To study the morphological alterations of MSA-C-affected brains in vivo using voxel-based morphometric analysis of magnetic resonance images. SETTING: University hospital. PATIENTS: Fourteen patients (5 men and 9 women) with MSA-C (mean age [SD], 59.4 [7.4] years; mean [SD] disease duration, 3.7 [1.4] years) and 13 healthy control subjects (5 men and 8 women) (mean [SD] age, 55.1 [6.9] years) were studied. METHODS: T1-weighted magnetic resonance images were normalized to a common stereotaxic space and segmented into gray and white matter. Data were analyzed using statistical parametric mapping (SPM99). RESULTS: Gray matter was reduced in the brainstem and the anterior lobe of the cerebellum. Reduction of white matter was observed in the middle cerebellar peduncles, cerebellar white matter, and brainstem. The inverted comparison revealed an increase of white matter density along the pyramidal tracts. CONCLUSIONS: Voxel-based morphometry revealed a significant loss of cerebellar and brainstem tissue in MSA-C. It allowed a precise anatomical localization and a distinction between gray and white matter densities. In addition, our data point to a particular involvement of the pyramidal tract in MSA-C.

Brain Stem↗
PubMed2004

Differences in [99mTc]TRODAT-1 SPECT binding to dopamine transporters in patients with multiple system atrophy and Parkinson's disease.

PURPOSE: Multiple system atrophy (MSA), a disorder causing autonomic dysfunction, parkinsonism, and cerebellar dysfunction, is difficult to differentiate from other movement disorders, particularly early in the course of disease. This study evaluated whether [99mTc]TRODAT-1 binding to the dopamine transporter differentiates MSA from other movement disorders. METHODS: Single-photon emission computed tomographic brain scans were acquired in 25 MSA patients, 48 age-matched controls, and 130 PD patients, 3 h after the injection of 740 MBq (20 mCi) of [99mTc]TRODAT-1. Regions of interest (ROIs) were placed manually on subregions of both basal ganglia and distribution volume ratios (DVRs) were calculated. Regional DVRs were compared between study groups in MSA patients. Student's t tests were used to compare MSA patients with other study groups. Spearman correlations were used to compare DVRs with NP measures. RESULTS: Based upon various motor scores, MSA and PD patients had comparable motor impairment, and were significantly impaired compared with controls. Mean DVRs in the basal ganglia of MSA patients were significantly less than those of controls, but generally higher (p<0.05) than in PD patients. In particular, the MSA patients had significantly increased DVRs in the posterior putamen (mean 0.49+/-0.30) compared with PD patients (0.74+/-0.25). CONCLUSION: Movement disorder patients could be differentiated from controls, but MSA and PD patients could not be easily differentiated from each other. As a group, MSA patients had significantly higher mean [99mTc]TRODAT-1 binding, particularly in the posterior putamen, compared with PD patients and significantly lower binding compared with controls. This may reflect different pathophysiological processes of the two neurodegenerative diseases.

Adult↗
PubMed1998

[Effective nasal CPAP therapy for heavy snoring and paradoxical respiration during sleep in a case of multiple system atrophy].

A 64-year-old man with multiple system atrophy complained of daytime sleepiness, fatigue, and snoring. Neurological examination revealed severe autonomic failure, mild cerebellar ataxia and akinesia. Daytime blood gas analysis showed respiratory acidosis with hypoxia and hypercapnia. MR imaging of the brain showed atrophy of the pons, cerebellum and bilateral frontal lobes. Although paralysis of the vocal cord abduction was not found by laryngoscopy during daytime examination, polysomnography (PSG) showed heavy snoring with paradoxical respiration associated with severe desaturation during sleep as well as reduced slow wave sleep and REM sleep. He was diagnosed as having sleep-related upper airway obstructive breathing disorder probably due to Gerhardt syndrome. Tracheostomy was considered, but we performed nasal CPAP therapy during sleep because this therapy is non-invasive and would not impair his daily life. After nasal CPAP therapy, daytime sleepiness, fatigue, and snoring with desaturation improved, and PSG showed increased slow wave sleep. These results demonstrate that nasal CPAP therapy improves the quality of sleep and should be considered in patients with early stages of multiple system atrophy who exhibit sleep-related breathing disorders.

Humans↗
PubMed1998

Cell death mechanisms in multiple system atrophy.

The presence and distribution of apoptotic cell death in multiple system atrophy (MSA) and morphologically related diseases were investigated by means of a modified terminal deoxynucleotidyl transferase-mediated nick end labeling method, comparing their distribution with that of glial cytoplasmic inclusions, immunohistochemically demonstrated bcl-2 protein, bax protein, CD95, TNFalpha, and p53-protein expression, as well as activated microglia. Apoptosis occurred almost exclusively in oligodendrocytes in multiple system atrophy and its general distribution was comparable to the already known oligodendroglial pathology in this disorder. Additionally, in about a quarter of glial cytoplasmic inclusions, there was upregulation of bcl-2-protein and coexpression with ubiquitin, suggesting a final attempt of involved cells to counteract apoptotic cell death. Bax protein was also demonstrated in oligodendroglial cells. A significant neuronal apoptosis was not observed in MSA; these cells might be destroyed secondarily to oligodendroglial apoptosis by necrosis or other forms of programmed cell death. These results emphasize the central role of oligodendroglial pathology in multiple system atrophy, making this disease unique among neurodegenerative diseases.

Adult↗
PubMed1997

Apolipoprotein E e4 allele frequency in patients with multiple system atrophy.

The glial cytoplasmic inclusion provides a histological hallmark for multiple system atrophy, a group of neurodegenerative disorders including: striatonigral degeneration, olivopontocerebellar atrophy, and Shy-Drager syndrome. Apolipoprotein E (APOE) genotype was determined by the polymerase chain reaction and restriction digestion of DNA extracted from frozen brain tissue from 22 patients (64.9 +/- 2.2 years) with clinically and neuropathologically verified multiple system atrophy (MSA). In addition, brain tissue from 36 age- and sex-matched patients who died with Alzheimer's disease (68.8 +/- 1.6 years) and 66 neurologically and psychiatrically normal subjects (66.6 +/- 1.8 years) was genotyped. The APOE e4 allele frequency in the Alzheimer's disease subjects was significantly increased (0.44, P < 0.001), as has been reported previously. The APOE e4 allele frequency of the MSA cases (0.11) was not significantly different from that of the control subjects (0.12). These data indicate that the APOE e4 allele is not a risk factor for multiple system atrophy.

Aged↗
PubMed1999

Alpha-synuclein immunoisolation of glial inclusions from multiple system atrophy brain tissue reveals multiprotein components.

Immunohistochemical studies have shown that oligodendroglial inclusions in multiple system atrophy contain alpha-synuclein, a synaptic protein also found in Lewy bodies in Parkinson's disease. We have now used density gradient enrichment and an anti-alpha-synuclein immunomagnetic technique to isolate pure and morphologically intact oligodendroglial inclusions from brain white matter of patients dying with multiple system atrophy. Filamentous inclusion structures were obtained only from multiple system atrophy tissue, but not from normal brain tissues, or from multiple system atrophy tissue processed without anti-alpha-synuclein antibody. We confirmed the purity and morphology of isolated inclusions by electron microscopy. The inclusions comprised multiple protein bands after separation by polyacrylamide gel electrophoresis. Immunoblotting demonstrated that these proteins included alpha-synuclein, alphaB-crystallin, tubulins, ubiquitin, and prominent, possibly truncated alpha-synuclein species as high-molecular-weight aggregates. Our study provides the first biochemical evidence that oligodendroglial inclusion filaments consist of multiple protein components, suggesting that these inclusions may form as a result of multiprotein interactions with alpha-synuclein.

Aged↗