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PubMed2002

[Delusional ectoparasitic infestation in multiple system atrophy].

Multiple system atrophy (MSA) is a neurodegenerative disease of unclear etiology and pathogenesis. Clinically, there are combinations of extrapyramidal, cerebellar, pyramidal and autonomic dysfunctions. Diagnosis is sorted into different categories according to criteria. The appearance of hallucinations unrelated to medication is considered to be a criterion of exclusion for the diagnosis of MSA. A case is described in which delusional parasitosis occurred as a possible initial syndrome of MSA. The simultaneous appearance of MSA and a psychotic disease is possible and has been described repeatedly. Therefore, this criterion of exclusion is discussed. Delusional parasitosis is an unspecific syndrome of multifactorial genesis. Partial remission of the monothematic symptomatology of delusion shows that a continuous and consequent therapy with neuroleptics seems to be promising. In the case presented, the good efficacy of olanzapine in low dosage over an extended period of time is described.

Basal Ganglia↗

PubMed2003

Multiple system atrophy.

Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder that usually manifests in the early fifties and progresses relentlessly with a mean survival of 9 years. Clinically, MSA is dominated by autonomic/urogenital failure which may be associated with either levodopa unresponsive parkinsonism in 80p.cent of cases (MSA-P subtype) or with cerebellar ataxia in 20p.cent of cases (MSA-C subtype). Pathologically, MSA is characterized by a neuronal multisystem degeneration and abnormal glial cytoplasmic inclusions containing alpha-synuclein aggregates. Pharmacological treatment of motor features is disappointing except for a transient L-Dopa response in a minority of MSA-P patients. In contrast, autonomic and urogenital features of MSA should be identified early on because they can be treated effectively in many instances. To improve the outcome of this devastating disorder which causes early severe and progressive disability more research into etiology, pathogenesis, early diagnosis and therapeutic management is necessary. Several research groups have been formed in Europe (EMSA-SG, NNIPPS) and USA (NAMSA-SG) to address these unmet needs.

Antiparkinson Agents↗

PubMed2005

Epidemiological evidence on multiple system atrophy.

Multiple system atrophy (MSA), is a sporadic neurodegenerative disorder characterized clinically by any combination of parkinsonian, autonomic, cerebellar or pyramidal symptoms and signs. The frequence of disease is estimated for the incidence rate to 0.6 cases per 100.000 person-years, while the prevalence rate is included between 1.86 and 4.9 cases per 100.000 pop. A risk factor seems to be the occupational history of farming also if the occupational exposure to pesticides is not associated with MSA. Smoking is probably a protective factor in MSA as Parkinson's disease. MSA seems a sporadic disease also if recently a German family with two MSA cases has been reported. The polymorphism association studies support a role for inflammation-related genes in risk for MSA. The current epidemiological and clinical evidence suggests that likely the etiopathogenesis of MSA is complex, and that many genetic as well as environmental factors are involved. Unfortunately, the most of studies in MSA are lacking in a sample size estimate to test the hypothesis, then the scientific evidence is poor. Then, much larger numbers of cases and controls are necessary for these studies to reach sufficient power, but collecting such large numbers is feasible only in the framework of multicentric consortia.

Animals↗

PubMed2002

New findings on the neuropathology of multiple system atrophy.

Multiple system atrophy (MSA) provides a typical example of the integrative role of the central autonomic network in controlling cardiovascular, respiratory, bladder and gastrointestinal functions. There is increasing evidence that neurochemically defined neuronal groups of the brainstem are selectively affected in MSA to a much greater degree than in Parkinson's disease. These include the catecholaminergic neurons of the rostral ventrolateral medulla (C1 group) which project to the intermediolateral cell column and are involved in modulation of sympathetic vasomotor outflow, and noradrenergic neurons of the caudal ventrolateral medulla (A1 group) projecting to the magnocellular nuclei of the hypothalamus and regulating vasopressin (AVP) release. Loss of these groups of neurons may, at least in part, explain the development of orthostatic hypotension, baroreflex dysfunction, and impaired reflex AVP release in response to hypotension. There is preliminary evidence that cardiovagal neurons of the ventrolateral portion of the nucleus ambiguus, distinct from the branchimotor neurons of the compact region, may also be affected in MSA. Loss of cholinergic neurons in the medullary arcuate nucleus, considered by some to be the homologous to the central chemosensitive region of the ventral medullary surface, may contribute to disturbances in automatic ventilation, particularly during sleep, in patients with MSA.

Catecholamines↗

PubMed2001

Sphincter EMG and differential diagnosis of multiple system atrophy.

Multiple system atrophy (MSA) is a degenerative disease manifesting a combination of parkinsonism, cerebellar, pyramidal, and autonomic (including urinary, sexual, and anorectal) dysfunction. It is pathomorphologically defined, but lacks a definitive clinical diagnostic test. Sphincter electromyography (EMG), reflecting Onuf's nucleus degeneration, has been proposed as a helpful test; its value has been reevaluated by a critical review of the literature. In patients with probable MSA, abnormal sphincter EMG, as compared to control subjects, has been found in the majority of patients in all the different forms of the disease in most studies, including patients who, as yet, have no urological or anorectal problems. The prevalence of abnormalities in the early stages of MSA is as yet unclear. Patients with Parkinson's disease (PD) as a rule do not show severe sphincter EMG abnormalities in the early stage of the disease. Anal sphincter EMG abnormalities (abnormal spontaneous activity or motor unit potential changes three standard deviations above valid control data) distinguish MSA from PD in the first 5 years after the onset of symptoms and signs, and from pure autonomic failure, as well as from cerebellar ataxias, if other causes for sphincter denervation have been ruled out. With such criteria, the sensitivity of the method is, however, low. EMG does not distinguish MSA from progressive supranuclear palsy. Future studies should use standardized anal sphincter EMG to better compare results from different centers and precisely define the sensitivity and specificity of the method.

Anal Canal↗

PubMed2004

A quantitative investigation of neuronal cytoplasmic and intranuclear inclusions in the pontine and inferior olivary nuclei in multiple system atrophy.

Multiple system atrophy (MSA) is a sporadic neurodegenerative disease characterized by the presence of neuronal and oligodendroglial alpha-synuclein aggregates. To investigate the relationship between the occurrence of neuronal cytoplasmic and intranuclear inclusions (NCIs and NNIs, respectively) and the progression of neuronal degeneration, we performed a quantitative analysis of the pontine and inferior olivary nuclei based on 14 cases of MSA. alpha-Synuclein immunohistochemistry revealed that NCIs and NNIs were present in both brain nuclei in all the cases. The average incidence of NCIs in the pontine and inferior olivary nuclei was 9.1% and 25.8%, respectively, and that of NNIs was 9.2% and 9.0%, respectively. The number of NNIs was strongly correlated with that of neurones in the pontine and inferior olivary nuclei. Although the number of NCIs was not correlated with the neuronal population in both nuclei, the NCI count in patients with moderate MSA was higher than in patients with mild MSA. The NNI count was much higher than the NCI count in the pontine nucleus in four patients, and was the same in the olivary nucleus in three of the four patients. Moreover, the neuronal population in the NNI-predominant cases was significantly higher than in the NCI-predominant cases. These findings suggest that NCI formation is accelerated by the progression of the disease process, and that in MSA, NNI formation is an earlier phenomenon than NCI formation.

Aged↗

PubMed2003

alpha-Synuclein fibrils constitute the central core of oligodendroglial inclusion filaments in multiple system atrophy.

Multiple system atrophy (MSA) belongs to synucleinopathies and is characterized pathologically by oligodendroglial inclusions (GCIs) composed of 20- to 30-nm tubular filaments. alpha-Synuclein fibrils formed in vitro, however, range between 10 and 12 nm in diameter. To understand the relationship between alpha-synuclein and GCI filaments, we conducted structural analyses of GCIs in fixed brain sections and isolated from fresh-frozen MSA brains. In fixed brain sections, GCIs were composed of amorphous material-coated filaments up to 30 nm in size. The filaments were often organized in parallel bundles extending into oligodendroglial processes. In freshly isolated GCIs, progressive buffer washes removed amorphous material and revealed that GCI filaments consisted of 10-nm-sized central core fibrils that were strongly alpha-synuclein immunoreactive. Image analysis revealed that each core fibril was made of two subfibrils, and each subfibril was made of a string of 3- to 6-nm-sized particles probably alpha-synuclein oligomers. Immunogold labeling demonstrated that epitopes encompassing entire alpha-synuclein molecule were represented in the core fibrils, with the N-terminal 11-26 and C-terminal 108-131 amino acid residues most accessible to antibodies, probably exposed on the surface of the fibril. Our study indicates that GCI filaments are multilayered in structure, with alpha-synuclein oligomers forming the central core fibrils of the filaments.

Aged↗

PubMed2005

Depressive symptoms and life satisfaction in patients with multiple system atrophy.

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by extrapyramidal signs, prominent autonomic failure, and a poor prognosis. In the absence of restorative treatment, management is aimed at improving quality of life. Little is known about modifiable factors, such as depression, that may affect quality of life in MSA. The present study investigated the rate of depressive symptoms and their relationship to life satisfaction in patients with MSA. Ninety-nine patients with MSA (54% women; mean age, 67.8 +/- 8.8) completed measures of depressive symptoms, life satisfaction, physical function, and disease and demographic factors. Objective autonomic indices were abstracted from the medical chart. Participants reported a high rate of depressive symptoms, with 39% endorsing moderate to severe depressive symptoms on the Beck Depression Inventory (BDI > or = 7). Reported life satisfaction was low, with a mean of 38.8 on a 100-point visual analogue scale (0 = Extremely Dissatisfied, 100 = Extremely Satisfied). The SF-36 Physical Component Scale was approximately 1.5 standard deviations below the mean of a normative sample of healthy adults the same age. Regression analysis revealed that autonomic disease parameters accounted for 22% of the variance in life satisfaction. Physical function did not account for any additional variance; however, depressive symptoms accounted for an additional 15%. Depressive symptoms are common, often severe, and an important determinant of life satisfaction in patients with MSA. Adequate treatment of comorbid depression may improve quality of life in this population, despite the presence of other debilitating deficits.

Aged↗

PubMed2005

Neurological and neurodegenerative alterations in a transgenic mouse model expressing human alpha-synuclein under oligodendrocyte promoter: implications for multiple system atrophy.

Multiple system atrophy (MSA) is a progressive, neurodegenerative disease characterized by parkinsonism, ataxia, autonomic dysfunction, and accumulation of alpha-synuclein (alpha-syn) in oligodendrocytes. To better understand the mechanisms of neurodegeneration and the role of alpha-syn accumulation in oligodendrocytes in the pathogenesis of MSA, we generated transgenic mouse lines expressing human (h) alpha-syn under the control of the murine myelin basic protein promoter. Transgenic mice expressing high levels of halpha-syn displayed severe neurological alterations and died prematurely at 6 months of age. Furthermore, mice developed progressive accumulation of halpha-syn-immunoreactive inclusions in oligodendrocytes along the axonal tracts in the brainstem, basal ganglia, cerebellum, corpus callosum, and neocortex. The inclusions also reacted with antibodies against phospho-serine (129) halpha-syn and ubiquitin, and halpha-syn was found in the detergent-insoluble fraction. In high-expresser lines, the white matter tracts displayed intense astrogliosis, myelin pallor, and decreased neurofilament immunostaining. Accumulation of halpha-syn in oligodendrocytes also leads to prominent neurodegenerative changes in the neocortex with decreased dendritic density and to loss of dopaminergic fibers in the basal ganglia. The oligodendrocytic inclusions were composed of fibrils and accompanied by mitochondrial alterations and disruption of the myelin lamina in the axons. Together, these studies support the contention that accumulation of alpha-syn in oligodendrocytes promotes neurodegeneration and recapitulates several of the key functional and neuropathological features of MSA.

Animals↗

PubMed2003

Tau and 14-3-3 in glial cytoplasmic inclusions of multiple system atrophy.

Multiple system atrophy (MSA) is a neurodegenerative disease characterized by the presence of glial cytoplasmic inclusions (GCIs), which are comprised of fibrils of the protein alpha-synuclein (alpha-syn). Increasing evidence indicate that the formation of these lesions leads to cellular dysfunction and degeneration. The events that result in the formation of GCIs remain poorly understood. It is possible that changes in the cytoplasmic milieu, perhaps the aberrant expression of alpha-syn-interacting proteins, can promote the polymerization of alpha-syn. The presence of the microtubule-binding protein, tau, in GCIs has been reported in some studies, but these findings have not been consistent, and these studies were performed prior to the availability of the more sensitive methods of detecting GCIs using anti-alpha-syn antibodies. Recently, 14-3-3 proteins, putative alpha-syn-interacting partners, have been reported in Lewy bodies, which also are pathological inclusions comprised of alpha-syn. In this study the presence of tau and 14-3-3 proteins in GCIs of 21 patients with MSA was investigated. For the majority of cases, tau and 14-3-3 proteins were detected only in a subset of GCIs. In some cases none of the GCIs contained 14-3-3 or tau. When present in GCIs, tau was in a hypophosphorylated state as demonstrated with phosphorylation-specific antibodies. Alpha-syn fibrillogenesis without 14-3-3 or tau appears to be sufficient for GCI formation, although it is possible that the accumulation of multi-functional proteins, like 14-3-3, in GCIs contribute to the disruption of cellular homeostasis.

14-3-3 Proteins↗

PubMed1997

Mitochondrial respiratory chain function in multiple system atrophy.

Multiple system atrophy (MSA) is a clinico-pathological entity distinct from idiopathic Parkinson's disease (PD) that is responsible for 5-10% of cases of parkinsonism. Degeneration of nigral neurones is a feature of both diseases. A specific deficiency of mitochondrial complex I activity has been found in PD substantia nigra. We have analysed mitochondrial function in substantia nigra and platelets from MSA patients to identify any respiratory chain defect in this disorder and to determine its tissue specificity. As our MSA patients had been on L-DOPA, we also sought to establish whether this treatment could cause the complex I defect as seen in PD. We found no significant difference in respiratory chain activity corrected for mitochondrial mass between control and MSA patients in either of the tissues studied. These results provide a biochemical dimension to the differences between MSA and idiopathic PD. In addition, the fact that L-DOPA failed to induce a complex I defect in MSA substantia nigra suggests that this treatment is unlikely to cause the complex I deficiency in PD, without additional factors that may operate in PD.

Aged↗

PubMed1991

Argyrophilic ubiquitinated cytoplasmic inclusions of Leu-7-positive glial cells in olivopontocerebellar atrophy (multiple system atrophy).

We described cytoplasmic inclusions in glial cells in 18 patients with olivopontocerebellar atrophy (OPCA) (multiple system atrophy, MSA). These glial inclusions showed intense argyrophilia with modified Bielschowsky's and Bodian's silver impregnation techniques, and were observed in the pons, cerebellar white matter, midbrain, medulla oblongata and basal ganglia, as well as cerebral white matter and spinal cord. None of the 54 control cases had glial argyrophilic inclusions. Immunohistochemically, these inclusions were intensely labeled by anti-ubiquitin antibody. Some of them reacted with an antibody to Rosenthal fiber (RF) protein. The cytoplasm of ubiquitinated inclusion-bearing glial cells was immunostained by anti-Leu-7 antibody, but not by anti-GFAP antibody. Ultrastructurally, the glial inclusions were composed primarily of approximately 24- to 40-nm fibrils, which were coated with osmiophilic granular material along their length in longitudinal section. These fibrils appeared as annuli in cross section. Often, a central granule approximately 5 nm in diameter was seen in the lucent lumen of a cross-sectioned fibril. The granule-coated fibrils were not seen in the glial filament-containing astrocytes. Electron microscopic examination of silver-impregnated specimens revealed that the granule-coated fibrils had strong affinity for silver. Immunoelectron microscopy using the indirect immunoperoxidase techniques with antibodies to ubiquitin and RF protein revealed that the electron-dense reaction products respective to both were located on constituents of glial inclusions. Our observation that Leu-7-positive glial cells, mainly oligodendroglial cells, had argyrophilic ubiquitinated inclusions may be of significance for the evaluation of the pathology of OPCA(MSA).

Adult↗

PubMed2000

[30 years multiple system atrophy concept: retrospect and overview of multiple system atrophy].

Multiple system atrophy represents an enigmatic, clinico-pathologically defined neurodegenerative disease. According to findings of the last three decades, the historically derived, previously used terms olivopontocerebellar atrophy, striatonigral degeneration, and Shy-Drager-syndrome should be avoided in clinical use because of both the clinical and morphological overlap between these syndromes. Complex neurodegenerative syndromes other than multiple system atrophy according to recently developed criteria, should rather be referred to as multiple system degenerations.

Adult↗

PubMed2002

Progressive cerebral atrophy in multiple system atrophy.

Nine patients with multiple system atrophy (MSA) were studied based on MRI findings of cerebral hemispheric involvement. The age at onset was 56.4+/-8.6 (mean+/-S.D.) years, duration of illness at the first MRI study 2.1+/-1.1 years, duration of illness at the last study 9.7+/-2.6 years, and the follow-up duration 7.6+/-2.3 years. Controls were 85 neurologically intact persons (60.2+/-11.1 years age). In the MRI study, measurements of the ratio of each area to the intracranial area were performed for the cerebral hemisphere, frontal, temporal and parietal-occipital lobes. A significant progression of atrophy to under the normal limit was observed in the cerebrum, frontal and temporal lobes. Besides the typical pathological lesions in MSA, five autopsied patients revealed frontal lobe atrophy with mild gliosis, mild demyelination and glial cytoplasmic inclusions (GCIs). One of these patients showed remarkable frontal lobe atrophy with degenerative changes in the cerebral cortex. We observed the involvement of the cerebral hemisphere, especially the frontal lobe.

Age of Onset↗

PubMed2002

[Quantitative MRI study of progressive cerebral atrophy in multiple system atrophy].

We investigated cerebral atrophy in multiple system atrophy (MSA) by quantitative analysis of MRI. The subjects were 28 patients with MSA (14 striato-nigral degeneration; SND, 14 olivo-ponto-cerebellar atrophy; OPCA. 106 MRI examinations were performed totally) and 85 normal persons for control. The ratios of the ventral pons to the infratentorial space in the sagittal section, the putamen, cerebrum, frontal lobe and parietal & occipital lobes to the intracranial space in the horizontal section, and the temporal lobe to the intracranial space in the coronal section were measured. In the early stage of the disease, OPCA showed significant atrophy of the ventral pons compared with SND, and conversely, SND demonstrated significantly smaller putamen than that in OPCA. According to the progression of the disease, the atrophy of these neural tissues progressed, which resulted in no significant differences between SND and OPCA. The cerebral atrophy was observed in 17 MSA patients. The atrophy of the frontal lobe was much frequent and prominent to that in the temporal lobe and parietal & occipital lobes. SND showed higher incidence of the cerebral atrophy than OPCA in the early stage of the disease. In long period follow-up cases, one case showed cerebral atrophy in earlier stage, and another case in late stage. We indicated the involvement of the cerebral hemispheres in MSA, especially the frontal lobe.

Aged↗

PubMed2000

Evolution of sporadic olivopontocerebellar atrophy into multiple system atrophy.

OBJECTIVE: To determine the percentage of sporadic olivopontocerebellar atrophy (sOPCA) patients who later develop multiple system atrophy (MSA). METHODS: Observations of the course of 51 sOPCA patients 20 years of age or older initially evaluated in an ataxia clinic over 14 years and followed at 3- to 6-month intervals for 3 months to 10 years (median 2.5 years, interquartile range 5 months to 4 years). RESULTS: Seventeen patients evolved to develop MSA, whereas the remaining 34 manifested only progressively worsening cerebellar ataxia. The features of the MSA cases included autonomic failure and parkinsonism in 10 patients, autonomic failure without parkinsonism in six, and parkinsonism without autonomic failure in one. Using survival analysis methods, the authors estimated that 24% of subjects in this population will evolve to MSA within 5 years of the onset of sOPCA symptoms (95% CI 10% to 36%). An older age at onset of symptoms and a shorter time from onset of symptoms to first presentation in a neurology specialty clinic were both highly predictive of evolution to MSA. Six of the 17 patients who evolved to MSA died 4 months to 5 years after they had met diagnostic criteria for MSA. The estimated median survival time from time of transition was 3.5 years. In contrast, death occurred in only one of the 34 patients with sOPCA who did not evolve to MSA. Autopsy examination of all six patients with MSA who died confirmed the diagnosis. CONCLUSIONS: Approximately one-fourth of sporadic olivopontocerebellar atrophy patients will evolve to multiple system atrophy within 5 years, and this transition carries a poor prognosis for survival. Older age at onset of ataxia and earlier presentation in a neurologic specialty clinic predicted transition to MSA.

Adult↗

PubMed1996

Decreased striatal monoaminergic terminals in olivopontocerebellar atrophy and multiple system atrophy demonstrated with positron emission tomography.

We used [11C]dihydrotetrabenazine, a new ligand for the type 2 vesicular monoamine transporter (VMAT2), with positron emission tomography to study striatal monoaminergic presynaptic terminals in 4 patients with multiple system atrophy, 8 with sporadic olivopontocerebellar atrophy, and 9 normal control subjects. Specific binding in the striatum was significantly reduced in the multiple system atrophy patients as compared with the normal control group, with average reductions of 61% in the caudate nucleus (p = 0.002) and 58% in the putamen (p = 0.009). Smaller reductions were found in the sporadic olivopontocerebellar atrophy group, averaging 26% in the caudate nucleus (p = 0.05) and 24% in the putamen (p = 0.11). Mean blood-to-brain [11C]dihydrotetrabenazine transport (K1) was significantly different between groups only in the cerebellum, with values for the sporadic olivopontocerebellar atrophy group diminished compared with the normal control group. Cerebellar K1 was not significantly decreased in the multiple system atrophy group. The finding of reduced striatal VMAT2 in sporadic olivopontocerebellar atrophy patients suggests nigrostriatal pathology, indicating that some may later develop symptomatic extrapyramidal disease.

Adult↗

PubMed2002

Different mechanism of vocal cord paralysis between spinocerebellar ataxia (SCA 1 and SCA 3) and multiple system atrophy.

While multiple system atrophy (MSA) is frequently associated with vocal cord paralysis (VCP) causing severe respiratory failure, it is still unknown whether hereditary types of spinocerebellar degeneration develop similar laryngeal paralysis. We analyzed the laryngeal function from the viewpoints of fiberoptic laryngoscopy and laryngeal myopathology and then attempted to clarify the difference of the mechanism of VCP among the patients with spinocerebellar ataxia type 1 (SCA 1), type 3 (SCA 3), and MSA. Seven patients with SCA 1, nineteen with SCA 3, and eleven with MSA were studied. Vocal cord movement was analyzed by fiberoptic laryngoscopy during wakefulness and diazepam-induced sleep (sleep load test). Paraffin-embedded sections or cryosections of the intrinsic laryngeal muscles from five autopsied cases (one with SCA 1 and four with SCA 3) were histologically examined. VCP was found in two of the seven SCA 1 patients (29%), three of the nineteen SCA 3 patients (16%), and in nine of the eleven MSA patients (82%). VCP observed in SCA 1 and SCA 3 was various in the severity and showed no exacerbation on sleep load test in all of the eight patients but one SCA 3 patient. In this patient, the findings of fiberoptic laryngoscopy were quite similar to those found in MSA. All the intrinsic laryngeal muscles including cricothyroid (CT), interarytenoid (IA), and posterior cricoarytenoid (PCA) muscles showed neurogenic atrophy in one autopsied SCA 1 and four SCA 3 patients. Our conclusion is that VCP in SCA 1 and SCA 3 contrasts with that in MSA in its occurrence, response to the sleep load test, and the distribution of the neurogenic abnormalities among the intrinsic laryngeal muscles.

Adult↗