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PubMed1999

Widespread alterations of alpha-synuclein in multiple system atrophy.

Glial cytoplasmic inclusions (GCI) are the hallmark of multiple system atrophy (MSA), a rare movement disorder frequently associated with autonomic dysfunction. In this study of 21 cases of MSA, GCI were consistently immunoreactive for alpha-synuclein and double-immunostained for ubiquitin and oligodendroglial markers, but not glial fibrillary acidic protein. No statistically significant difference was found in the density of GCI in various brain regions in the two forms of MSA, striatonigral degeneration (SND) and olivopontocerebellar atrophy (OPCA). Postmortem brain samples from 9 cases of MSA were fractionated according to solubility in buffer, Triton-X 100, sodium dodecyl sulfate (SDS), and formic acid, and alpha-synuclein immunoreactivity was measured in Western blots. Total alpha-synuclein immunoreactivity was increased in MSA compared to controls, with no statistically significant difference between SND and OPCA. Most of the increase was due to alpha-synuclein in SDS fractions. In controls this fraction had little or no immunoreactivity. In 7 cases and 4 controls correlations were investigated between quantitative neuropathology and biochemical properties of alpha-synuclein. Surprisingly, the amount of SDS-soluble alpha-synuclein correlated poorly with the number of GCI in adjacent sections. Furthermore, areas with few or no GCI unexpectedly had abundant SDS-soluble alpha-synuclein. These findings provide evidence that modifications of alpha-synuclein in MSA may be more widespread than obvious histopathology. Moreover, these alterations may constitute a biochemical signature for the synucleinopathies.

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PubMed2002

Patterns of neuropsychological performance in multiple system atrophy compared to sporadic and hereditary olivopontocerebellar atrophy.

Although neuropsychological symptoms are associated with multiple system atrophy (MSA), sporadic olivopontocerebellar atrophy (sOPCA), and dominantly inherited olivopontocerebellar atrophy (dOPCA), the differences between these groups have not been explored. We compared 28 MSA patients on psychiatric rating scales and neuropsychological measures to 67 sOPCA patients, 42 dOPCA patients, and 30 normal controls. Patients with dOPCA, sOPCA, and MSA all exhibited significant deficits on motor-related tasks, as well as relatively mild deficits in cognitive functioning. Patients with MSA had greater neuropsychological dysfunction, particularly in memory and other "higher order" cognitive processes, than patients with either sOPCA or dOPCA.

Cognition Disorders↗

PubMed2006

Cerebral vasomotor reactivity in Parkinson's disease, multiple system atrophy and pure autonomic failure.

Parkinson's disease (PD), multiple system atrophy (MSA) and pure autonomic failure (PAF) are neurodegenerative disorders frequently associated with orthostatic hypotension and syncope, though with different underlying mechanisms. Cerebral hemodynamic responses in these three neurodegenerative diseases are still incompletely studied and it is possible that they would be differentially affected. We measured blood flow velocity (BFV) in the middle cerebral artery (MCA) and vertebral artery (VA) in patients with these disorders and investigated whether cerebral vasomotor reactivity (VMR) differs in these three disorders. Twenty-four patients (9 with PD, 10 with MSA and 5 with PAF) were studied. VMR was assessed in the MCA and VA, using transcranial Doppler (TCD) and Diamox test (injection of 1 g acetazolamide i.v.) with the patients in a recumbent position. The percent difference between BFV before and after acetazolamide injection was defined as VMR% and the results were compared by ANOVA. The mean MCA and VA blood flow velocities were similar in the three disorders and within normal limits for our laboratory. The mean MCA VMR values were 37.5+/-24.0%, 27.9+/-28.0% and 38.0+/-33.9% in PD, MSA and PAF, respectively. The VA VMR values were 22.9+/-23.6%, 32.4+/-38.0% and 18.9+/-18.3%, respectively, with no significant differences between the groups. We conclude that BFV is normal in PD, MSA and PAF and that the VMR, as investigated by TCD and the Diamox test, did not disclose differences in cerebral vasomotor responses between these conditions.

Acetazolamide↗

PubMed2003

Videofluoroscopic and manometric evaluation of swallowing function in patients with multiple system atrophy.

We investigated swallowing function of 29 patients with multiple system atrophy (MSA) by videofluoroscopy and manometry. Abnormal findings in videofluoroscopy were generally consistent with those in Parkinson's disease. Although findings of videofluoroscopy were not correlated with a history of aspiration pneumonia, severity of disease was significantly correlated with a history of aspiration pneumonia. Oropharyngeal and hypopharyngeal swallowing pressures of the patients were decreased to 73.9 +/- 48.4 mm Hg and 85.3 +/- 42.9 mm Hg, respectively, both of which were significantly different from the pressures of the control group. Incomplete relaxation of the upper esophageal sphincter was seen in 23.1% of the MSA patients, all of whom had had MSA for more than 5 years. In conclusion, patients with MSA are at risk for aspiration pneumonia as disease severity increases, and the swallowing function of patients with more than 5 years' duration of MSA should be routinely followed up with both videofluoroscopy and manometry.

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PubMed2001

Epidemiology of multiple system atrophy. ESGAP Consortium. European Study Group on Atypical Parkinsonisms.

Multiple system atrophy (MSA) is a form of atypical parkinsonism with unknown etiology. The epidemiological studies conducted up to now on this disease are scarce. The incidence rate is about 0.6 cases per 100,000 persons per year. The prevalence rates show 4-5 cases per 100,000 persons. In Italy, about 4,900 prevalent cases have been estimated. The mean onset age is about 54 years; the median survival is 7-9 years. Only one case-control study has been performed on this disease. This study showed an increased risk of MSA associated with occupational exposure to organic solvents, plastic monomers and additives, pesticides and metals. Smoking habits seem to be less frequent in MSA cases (as in Parkinson's disease cases) than in healthy controls. Quinn's clinical criteria and those of the Consensus Conference promoted by the American Academy of Neurology are in fair agreement. We have performed a case-control study on 73 MSA cases, 146 hospital controls and 73 population controls.

Age of Onset↗

PubMed2002

Alpha-synuclein immunoreactivity and ultrastructural study of glial cytoplasmic inclusions in multiple system atrophy.

OBJECTIVE: To understand the possible pathogenesis of sporadic multiple system atrophy (MSA). METHODS: The immunoreactivity and ultrastructural features of glial cytoplasmic inclusions (GCIs) in 12 autopsy patients with MSA and 4 normal control groups were studied. All regional sections from each subject were evaluated with HE staining, Klüver-Barrera (KB), Holzer's, modified Gallyas-Braak's (GB) methods and immunohistochemical staining with alpha-synuclein and ubiquitin antibodies. Pontine white matter with abundant GCIs from case 1 was examined, using conventional electron microscopy, Gallyas-Braak's electron microscopy and immunoelectron microscopy. RESULTS: The presence of GCIs as constantly demonstrated in all MSA patients. Strong alpha-synuclein immunoreactivity was observed in all of the ubiquitinated GCIs. However, the density of alpha-synuclein positive GCIs differed from case to case, and there was no relationship between the density of GCIs and age, sex, or MSA subtype. Ultrastructural features indicated that argyrophilic granule-associated filaments of about 25 nm in diameter were the predominant constituents of GCIs, and the anti alpha-synuclein antibody selectively labeled in these filaments. No GCIs and alpha-synuclein immunoreaction were found in control brain tissues. CONCLUSIONS: GCI was a pathognomonic change in sporadic MSA patients. Accumulation of alpha-synuclein in GCIs may occur during the early stags of MSA. Seletcive alpha-synuclein positive abnormal microtubules in GCIs therefore play an important role in the pathogenesis of MSA.

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PubMedDate not supplied

Towards neurotransplantation in multiple system atrophy: clinical rationale, pathophysiological basis, and preliminary experimental evidence.

Multiple system atrophy (MSA) is a neurodegenerative disorder that occurs sporadically and causes parkinsonism, cerebellar, autonomic, urinary, and pyramidal dysfunction in many combinations. Progressive L-dopa-unresponsive parkinsonism due to underlying striatonigral degeneration dominates the clinical syndrome in the majority of cases (MSA-P subtype). MSA-P is characterized pathologically by degenerative changes in somatotopically related areas of the substantia nigra pars compacta and of the putamen. Furthermore, oligodendroglial cytoplasmic inclusions (GCIs) are observed throughout the cortico-striato-pallidocortical loops and may contribute to the basal ganglia dysfunction. Neurotransplantation strategies are of potential interest in this disease, which causes marked and early disability and dramatically reduces life expectancy. A number of experimental MSA-P models have been employed to evaluate neurotransplantation approaches. Sequential nigral and striatal lesions using 6-hydroxydopamine and quinolinic acid (double toxin-double lesion approach) indicate that apomorphine-induced contralateral rotation is abolished by a secondary striatal lesion. Intrastriatal injection of mitochondrial respiratory chain toxins produces secondary excitotoxic striatal lesions combined with retrograde nigral degeneration and therefore provides an alternative single toxin-double lesion approach. Neurotransplantation in MSA-P animal models has been used to improve functional deficits by replacing lost nigral and/or striatal circuitry (neuroregenerative approach). The available data indicate that embryonic mesencephalic grafts alone or combined with striatal grafts partially reverse drug-induced rotation asymmetries without improving deficits of complex motor function. The potential neuroprotective efficacy of embryonic striatal grafts against striatal excitotoxicity is presently under investigation in the double toxin-double lesion MSA-P rat model. Anecdotal clinical evidence in one MSA-P patient misdiagnosed as Parkinson's disease indicates that embryonic mesencephalic grafts produce incomplete clinical benefit. Striatal co-grafts may increase functional improvement. Further experimental studies are required prior to the clinical application of embryonic neurotransplantation in MSA-P. Future research strategies should explore the effect of neurotransplantation in partial MSA-P rat models with less severe nigral and striatal degeneration, the feasibility of a primate model closely mimicking the human disease, and the replication of oligodendroglial dysfunction.

Animals↗

PubMed1999

Multiple system atrophy: the putative causative role of environmental toxins.

BACKGROUND: Whereas a number of studies have investigated the putative role of environmental toxins in the pathogenesis of idiopathic Parkinson disease, the possibility of such a role in multiple system atrophy has received little attention. DESIGN AND SETTING: Review of records of patients examined in the Parkinson's Disease Center and Movement Disorder Clinic, Baylor College of Medicine, Houston, Tex, from July 1, 1977, to February 4, 1998. PATIENTS: We reviewed 100 consecutive medical records of patients who satisfied the diagnostic criteria for multiple system atrophy formulated by the Consensus Committee of the American Autonomic Society and the American Academy of Neurology. INTERVENTION: The type and amount of toxin exposure were verified by history and examination of records whenever possible. Severity of parkinsonism was assessed by clinical rating scales. MAIN OUTCOME MEASURE: Development of multiple system atrophy after environmental toxin exposure. RESULTS: Eleven patients had a notable history of heavy exposure to environmental toxins. One patient with multiple system atrophy confirmed by postmortem evaluation was exposed to high concentrations of malathion, diazinon, and formaldehyde, while the other patients with multiple system atrophy had well-documented high exposures to agents including n-hexane, benzene, methyl isobutyl ketone, and pesticides. The case studied pathologically demonstrated extensive advanced glial changes, including glial cytoplasmic inclusions in deep cerebellar white matter, brainstem, cortex (superior frontal, insula) and putamen, with notable cell loss and depigmentation of the substantia nigra and locus ceruleus. CONCLUSION: While many studies report a possible role of environmental toxins in Parkinson disease, such a role is even more likely in multiple system atrophy, as this is a sporadic disease.

Environmental Pollutants↗

PubMed1994

Genitourinary dysfunction in multiple system atrophy: clinical features and treatment in 62 cases.

Multiple system atrophy is a disorder characterized by progressive neuronal atrophy at certain sites of the central nervous system, several of which are important in the control of urogenital function. The neuro-urological features of 62 patients with this condition are described. All patients had abnormal urethral or anal sphincter electromyography when individual motor unit analysis was performed, a finding diagnostic of the condition in the appropriate clinical setting. Impotence occurred in 96% of the men and was the first symptom alone in 37%. Urinary symptoms resulted from a combination of detrusor hyperreflexia and urethral sphincter weakness followed by failure of detrusor contraction. In men these symptoms simulated those of outflow obstruction so that 43% underwent prostatic or bladder neck surgery before the correct diagnosis was made. Stress incontinence occurred in 57% of the women and of these half had undergone surgery. The results of surgery in both sexes were poor. Treatment with intermittent catheterization, anticholinergic medication and desmopressin spray markedly improved continence in 82%. The importance of recognizing this disorder and introducing effective, nonoperative treatments is stressed.

Adult↗

PubMed1986

Urethro-vesical dysfunction in progressive autonomic failure with multiple system atrophy.

Fourteen patients with progressive autonomic failure and multiple system atrophy have been investigated by urodynamic, electromyographic and neurohistochemical means and the results compared with a series of age-matched controls. Three fundamental abnormalities of lower urinary tract function have been identified: (1) Involuntary detrusor contractions in response to bladder filling. It is suggested that these may be the result of a loss of inhibitory influences from the corpus striatum and substantia nigra. (2) Loss of the ability to initiate a voluntary micturition reflex. This may reflect the degeneration of neurons in pontine and medullary nuclei and in the sacral intermediolateral columns. In addition, these studies have demonstrated a significant reduction in the density of acetylcholinesterase-containing nerves in bladder muscle. (3) Profound urethral dysfunction. This appears to be partly due to a loss of proximal urethral sphincter tone, which causes bladder neck incompetence. In addition, the function of the striated component of the urethral sphincter is impaired. Individual motor units recorded from this muscle were clearly abnormal when compared with controls and suggested that reinnervation had occurred. We suggest that this is the result of degeneration of a specific group of sacral anterior horn cells known as Onuf's nucleus. The evidence that these particular motor units are affected, while others are spared, poses fundamental questions about the nature of selective vulnerability in degenerative diseases of the nervous system.

Acetylcholinesterase↗

PubMed1992

The dopaminergic response in multiple system atrophy.

Fifteen of 23 pathologically confirmed cases of multiple system atrophy (MSA) showed some initial response to levodopa and eight of these remained at least partially responsive at the time of death. Eleven developed motor oscillations, and drug-induced dyskinesias, often involving the face and jaw, were also seen in 11 cases. Acute levodopa and apomorphine challenges were administered to 11 patients with clinical MSA who were considered levodopa responsive. A short duration relatively small amplitude response with associated dyskinesias occurred in six and a further three developed dyskinesias without any motor response. Following levodopa withdrawal, a delayed deterioration occurred after three to six days in six patients, five of whom had shown no short duration motor response to the acute challenges. The occurrence of levodopa-induced dyskinesias without a concomitant motor response and delayed deterioration several days after levodopa withdrawal may be more typical of patients with MSA than Parkinson's disease.

Adult↗

PubMed1994

Survival of patients with multiple system atrophy.

We investigated the survival of patients with multiple system atrophy (MSA) in a follow-up study of 59 patients admitted to Nagoya University Hospital between 1976 and 1991. They consisted of 24 patients with olivopontocerebellar atrophy (OPCA), 25 with Shy-Drager syndrome (SDS) and 10 with striatonigral degeneration (SND). The mean age at onset was 54 years, the 3-year survival rate from onset was 90%, and the 6-year survival rate was 54%. Comparison of survival curve by clinical type revealed poorer survival in SDS and SND than in OPCA cases. Although in OPCA, SND and SDS the pathological alterations of the central nervous system are known to be very similar, characterized as MSA, the present study suggests that the earlier and the more severe the involvement of the autonomic nervous system, and to a lesser extent the striatonigral system, the poorer the prognosis may be.

Adult↗

PubMed1998

Clinical usefulness of magnetic resonance imaging in multiple system atrophy.

OBJECTIVES: To determine the sensitivity, specificity, and positive predictive values of a selection of abnormal findings in the putamen and infratentorial structures on routine magnetic resonance imaging for distinguishing between multiple system atrophy, idiopathic Parkinson's disease, and age matched controls. PATIENTS AND METHODS: Two neuroradiologists blindly and independently rated axial T2 weighted and proton density MRI of 44 patients with multiple system atrophy, 47 patients with idiopathic Parkinson's disease, and 45 controls. High field (1.5 T) scans were available in 16 patients with multiple system atrophy, 15 patients with idiopathic Parkinson's disease, and 16 controls. All other patients had 0.5 T scans. RESULTS: On both 0.5 and 1.5 T scans the following items had high specificity but low sensitivity: putaminal atrophy, a hyperintense putaminal rim, and infratentorial signal change. Finding any infratentorial abnormality gave higher sensitivity but lower specificity. Putaminal isointensity or hypointensity relative to globus pallidus, absolute putaminal hypointensity, and altered size of the olives were not useful discriminators. The overall sensitivity was 73% on 0.5 T and 88% on 1.5 T scans. The specificities of these findings for multiple system atrophy in comparison to idiopathic Parkinson's disease and controls on 0.5 T were 95% and 100% respectively, and on 1.5 T were 93% and 91% respectively. Finding any of the described abnormalities on MRI gave a positive predictive value of 93% on the 0.5 T machine, and 85% on the 1.5 T scanner.

Adult↗

PubMed2005

Alpha-synuclein binding to rab3a in multiple system atrophy.

Glial cytoplasmic inclusions (GCIs) are characteristic protein deposits in multiple system atrophy (MSA), which are composed of abnormally phosphorylated, partially insoluble alpha-synuclein. In addition, recent studies have shown abnormal widespread accumulation of alpha-synuclein in neurons and neuronal processes, and in several regions including the thalamus and cerebral cortex in MSA. Combined alpha-synuclein and rab3a immunoprecipitation assays have shown alpha-synuclein/rab3a binding in the cerebellum and pons (in which GCIs were present) and in the cerebral cortex (area 8) (in which GCIs were absent) in MSA cases, but not in the cerebellum and cerebral cortex in age-matched controls. Similar findings were found in MSA-C and MSA-P cases (olivopontocerebellar atrophy and striatonigral degeneration types, respectively), thus indicating possible abnormal interactions of alpha-synuclein and rab3a in diseased brains. Abnormal alpha-synuclein binding to rab3a was also found in the substantia nigra but not in the cerebral cortex in Parkinson's disease. These findings suggest membrane and synaptic vesicle trafficking as vulnerable targets in MSA. Since rab3a is a member of the Ras super-family of small (21-25 kDa) GTP-binding proteins which is involved in the regulation of the internal trafficking, exocytosis and neurotransmission, and vesicle endocytosis, the present findings might suggest membrane and synaptic vesicle trafficking as vulnerable targets in MSA.

Blotting, Western↗

PubMed2005

Functional imaging with positron emission tomography in multiple system atrophy.

Although the current guidelines for the clinical diagnosis of multiple system atrophy (MSA) do not require structural or functional brain imaging, investigations utilizing positron emission tomography (PET) have been helpful diagnostically in differentiating between MSA and primary autonomic failure; idiopathic Parkinson's disease; and sporadic olivopontocerebellar atrophy. These investigations have demonstrated different patterns of cerebral glucose utilization and of nigrostriatal projection abnormalities among these disorders and between the cerebellar and parkinsonian forms of MSA. Most of the studies have focused upon patients with well-established disease and none have examined the utility of PET imaging in early stage patients with follow-up of clinical course and autopsy verification to ensure accuracy of diagnosis and to determine the sensitivity and specificity of PET techniques for diagnosis. Recent PET studies have revealed denervation of myocardial post-ganglionic sympathetic neurons in some MSA patients, indicating that this disorder can affect the peripheral autonomic as well as the central nervous system. Investigations utilizing ligands to quantify central nervous system dopaminergic and cholinergic terminals have begun to provide insight into the neurochemical disorders that may underlie two of the sleep disturbances common in MSA, rapid eye movement sleep behavior disorder and obstructive sleep apnea.

Animals↗

PubMed2001

Depletion of corticotrophin-releasing factor neurons in the pontine micturition area in multiple system atrophy.

We sought to determine whether the putative pontine micturition center in the human dorsal pons contains corticotrophin-releasing factor (CRF) neurons, and whether these neurons are depleted in patients with multiple system atrophy and bladder dysfunction. Brains were obtained at autopsy from 4 control subjects and 4 patients with clinical diagnosis of multiple system atrophy, confirmed neuropathologically. Serial 50 microm cryostat sections were obtained throughout the rostral half of the pons, and every eighth section was processed for CRF immunocytochemistry (rabbit polyclonal antibody). Consecutive sections were stained for nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) to identify neurons of the laterodorsal tegmental nucleus or for both CRF and NADPH. Locus ceruleus neurons were identified by their neuromelanin content. Abundant CRF immunoreactive neurons were identified in the dorsal pontine tegmentum just ventral to the locus ceruleus. CRF neurons were intermingled with, but distinct from, the NADPH-d-reactive neurons of the laterodorsal tegmental nucleus. In all multiple system atrophy cases, there was a severe depletion of these CRF-immunoreactive neurons (26.6 +/- 3 neurons/section in patients; 73.7 +/- 4 neurons/section in controls). Our results suggest that depletion of CRF neurons in the putative pontine micturition center may contribute to the severe bladder dysfunction that characterizes multiple system atrophy.

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PubMed1999

Cardiac uptake of [123I]MIBG separates Parkinson's disease from multiple system atrophy.

OBJECTIVE: To improve the differential diagnosis between patients with multiple system atrophy (MSA) and idiopathic PD (IPD) with autonomic failure. BACKGROUND: Some patients diagnosed with IPD are discovered to have alternative diseases such as MSA, despite the application of stringent diagnostic criteria. This differentiation is particularly difficult if patients with IPD also show symptoms of autonomic failure. In IPD, autonomic failure is caused by damage of the postganglionic part of the autonomic nervous system, whereas in MSA, degeneration of preganglionic and central autonomic neurons is revealed histopathologically. METHODS: Scintigraphy with [123I]metaiodobenzylguanidine (MIBG) enables the quantification of postganglionic sympathetic cardiac innervation. Fifteen patients with IPD and 5 patients with MSA underwent standard autonomic function tests and scintigraphy with MIBG. RESULTS: In all patients, cardiovascular testing showed evidence of autonomic failure of varying severity. In all patients with IPD, the heart-mediastinum (H/M) ratio of MIBG uptake was pathologically impaired, independent of duration and severity of autonomic and parkinsonian symptoms. All patients with MSA had a regular H/M ratio. Each patient could be assigned to the correct diagnostic group based on the results of the MIBG scintigraphy, even if the duration of the disease was only 2 years or less. CONCLUSIONS: This population assessment of the heart-mediastinum ratio of [123I]metaiodobenzylguanidine uptake showed a high sensitivity for the detection of autonomic involvement in patients with idiopathic IPD and also a high specificity for the discrimination between idiopathic PD and MSA.

3-Iodobenzylguanidine↗

PubMed2002

Pathology of the inferior olivary nucleus in patients with multiple system atrophy.

The inferior olivary nucleus (ION) from nine patients with multiple system atrophy was examined with antibodies against alpha-synuclein, ubiquitin, synaptophysin, glial fibrillary acidic protein, the Golgi apparatus (GA)-trans-Golgi network (TGN), and microglia/macrophages. As previously reported, there were neuronal loss, gliosis, and alpha-synuclein-positive cytoplasmic inclusions in neurons and glia. In addition, all neurons with alpha-synuclein-positive cytoplasmic inclusions contained abnormal profiles of the GA and TGN, which were reduced in size and numbers. This finding suggests a relationship between the pathogenetic mechanisms causing inclusion body formation and abnormalities of the GA-TGN. This study is also consistent with the conclusion that lesions of the ION may not always reflect changes of transsynaptic degeneration secondary to Purkinje cell loss.

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