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PubMed1980

Lateral horn cells in progressive autonomic failure.

Estimates of cell loss in the intermediolateral columns of the thoracic cord in cases of progressive autonomic failure were made by counting nerve cells in the lateral grey horns from 21 such cases, and comparing (a) with "normal" controls, (b) with 3 cases of uncomplicated Parkinson's disease and (c) with 3 cases of multiple system atrophy without overt autonomic failure. It was found that all cases of autonomic failure had suffered severe cell loss; on average three quarters of their lateral horn cells were lost. The cases of uncomplicated Parkinson's disease did not differ from the controls; but the cases of multiple system atrophy without autonomic disturbances had lost about half their lateral horn cells. These findings are tabulated, and discussed.

Aged↗

PubMed1981

Pathology of the intrinsic muscles of the larynx.

The intrinsic muscles of the larynx were exposed in each of 54 normal larynges derived from the autopsy series of a general hospital and submitted to microscopic examination. Muscle fibre alterations were found in all the posterior cricocarytenoid muscles in patients from 13 years of age on wards. In about half of the patients these changes included necrosis of segments of muscle fibres and secondary cellular reactions to this. In two cases of chronic autonomic failure with multiple system atrophy the intrinsic laryngeal muscles were similarly examined. Both cases showed a marked gross and microscopic atrophy of the posterior cricoarytenoid muscles; there were also microscopic changes similar to those found in the normal population. The significance of the changes in the routine post-mortem larynges, the changes in the cases of chronic autonomic failure with multiple system atrophy and the relationship between the two are discussed.

Adolescent↗

PubMed1993

Chemical mediators of autonomic nervous system activity.

Several modifications have improved the sensitivity and specificity of neurochemical tests to diagnose and distinguish multiple system atrophy and pure autonomic failure. These include [3H]-norepinephrine infusion to estimate plasma norepinephrine clearance; neuroendocrine stimulation tests; and simultaneous measurements of levels of levodopa, catecholamines, and catecholamine metabolites. New clinical imaging approaches have the potential to visualize alterations in neurotransmitter function in the brain and periphery. Patients with multiple system atrophy have decreased striatal radioactivity after injection of positron-emitting ligands at dopamine receptors or uptake sites, and patients with diffuse sympathetic denervation have decreased myocardial radioactivity after injection of radioactive sympathoneural imaging agents.

Autonomic Nervous System↗

PubMed1989

Treatment of orthostatic hypotension with octreotide.

The purpose of this study was to evaluate the therapeutic potential of the somatostatin analog octreotide in patients with orthostatic hypotension. Octreotide was administered sc, and its pressor effect was assessed while the patients were semirecumbent and on the tilt table. We also studied the effect of octreotide on blood pressure while patients walked. The efficacy of therapy was assessed by measuring the duration of walking (walking time) before the onset of hypotension. Low doses of octreotide (0.2-0.4 micrograms/kg) had a pressor effect in all patients with progressive autonomic failure (n = 7), multiple system atrophy (n = 7), and diabetic autonomic neuropathy (n = 8), but not in patients with sympathotonic orthostatic hypotension (n = 6). Larger doses (0.4-1.6 micrograms/kg) resulted in a sustained (greater than or equal to 50 min) increase in blood pressure during walking in four of six patients with progressive autonomic failure and in one of six patients with multiple system atrophy. Some patients in whom octreotide failed to stabilize upright blood pressure had a satisfactory response to the drug after pretreatment with dihydroergotamine (10 micrograms/kg, sc). Patients with diabetic autonomic neuropathy, although sensitive to the pressor effect of octreotide, often developed nausea or abdominal cramps after moderate doses (greater than 1.0 micrograms/kg). These results indicate that the pressor effect of octreotide is sufficiently potent to prevent orthostatic hypotension in some patients with autonomic neuropathy. Others require treatment with both dihydroergotamine and octreotide to achieve a stable upright blood pressure.

Adult↗

PubMed1983

Neuropathology of the locus ceruleus: a semi-quantitative study.

The locus ceruleus was studied in 86 brains of the elderly, with or without degenerative disease. Parkinson's disease, multiple system atrophy, progressive supranuclear palsy and senile dementia were among the diseases studied. Nerve cell loss, the appearance of neurofibrillary changes and Lewy bodies were examined semi-quantitatively. The number of nerve cells diminished in old age, especially over 90 years. The decrease of nerve cells was greater in cases with Lewy bodies. A marked loss of nerve cell was observed in multiple system atrophies, including Shy-Drager syndrome, olivopontocerebellar atrophy and striatonigral degeneration, and in some cases of Parkinson's disease and senile dementia. The number of nerve cells did not decrease in cases of progressive supranuclear palsy. Lewy bodies and neurofibrillary tangles appeared increasingly in old age. However, the incidence of both changes in the same neuron was rare, and in such cases their structures appeared not to be related.

Aged↗

PubMed2002

NACP/alpha-synuclein immunoreactivity in diffuse neurofibrillary tangles with calcification (DNTC).

Diffuse neurofibrillary tangles with calcification (DNTC) is a rare tangle-predominant dementia, as well as one of the tauopathies lacking Abeta deposition. It is characterized by temporo-frontal lobar atrophy, Fahr-type calcification and, histopathologically, numerous neurofibrillary tangles in the limbic system and neocortex. Recently, accumulation of alpha-synuclein (alphaS), the precursor of the non-beta amyloid component (NAC) of Alzheimer's disease, has been shown in diverse neurodegenerative disorders, including Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease, multiple system atrophy and parkinsonism-dementia complex of Guam. To clarify whether alphaS accumulates in other neurodegenerative disorders, we investigated eight DNTC brains using immunohistochemistry and demonstrated remarkable alphaS deposition in the neurons and astrocytes in many anatomical regions. Abundant Lewy bodies were observed in the amygdala (seven cases) and hippocampus (seven cases), and, to a lesser degree, in the substantia nigra (six cases) and dorsal vagal nucleus (five cases). In the hippocampus, many Lewy neurites were distributed in the stratum oriens and stratum pyramidale in the CA2-3 and the subiculum. Furthermore, numerous NAC-positive astrocytes were detected in the hippocampus and temporal cortex. This investigation reveals that neurons and astrocytes are extensively involved in remarkable alphaS pathology in the DNTC brain, and that the alphaS pathology compounds the cardinal pathological features of tau pathology. These findings suggest that (1) DNTC shares a common pathophysiological background with Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy in which abnormal alphaS aggregation is observed, and (2) there is an interaction between alphaS and tau pathology that does not involve amyloid in DNTC.

Adult↗

PubMed1987

Atypical Gerstmann-Straüssler syndrome or familial spinocerebellar ataxia and Alzheimer's disease?

We report a neuropathologic study of a case with features of Gerstmann-Straüssler syndrome (GSS) that is remarkable for the large number of neurofibrillary tangles (NFTs) throughout the neuraxis. The patient had a family history of spinocerebellar ataxia, but without dementia in other affected members. Our case meets the cardinal features of GSS as a rare familial degenerative disease characterized by clinically, spinocerebellar ataxia accompanied by progressive dementia, and pathologically, multiple system atrophy combined with widespread amyloid plaque deposition in the cerebral and cerebellar cortex. However, most pathologic studies stress the absence of NFTs in GSS. The nosology of this case is difficult to resolve because of profuse NFTs and morphologic differences between our and comparison Alzheimer's disease (AD) cases, the most prominent being spongiform changes. This case is remarkable because it combines features of a number of CNS degenerative diseases, including multiple system atrophy, AD, spongiform encephalopathies, and cerebrovascular amyloidosis.

Aged↗

PubMed2004

p25alpha Stimulates alpha-synuclein aggregation and is co-localized with aggregated alpha-synuclein in alpha-synucleinopathies.

Aggregation of the nerve cell protein alpha-synuclein is a characteristic of the common neurodegenerative alpha-synucleinopathies like Parkinson's disease and Lewy body dementia, and it plays a direct pathogenic role as demonstrated by early onset diseases caused by mis-sense mutations and multiplication of the alpha-synuclein gene. We investigated the existence of alpha-synuclein pro-aggregatory brain proteins whose dysregulation may contribute to disease progression, and we identified the brain-specific p25alpha as a candidate that preferentially binds to alpha-synuclein in its aggregated state. Functionally, purified recombinant human p25alpha strongly stimulates the aggregation of alpha-synuclein in vitro as demonstrated by thioflavin-T fluorescence and quantitative electron microscopy. p25alpha is normally only expressed in oligodendrocytes in contrast to alpha-synuclein, which is normally only expressed in neurons. This expression pattern is changed in alpha-synucleinopathies. In multiple systems atrophy, degenerating oligodendrocytes displayed accumulation of p25alpha and dystopically expressed alpha-synuclein in the glial cytoplasmic inclusions. In Parkinson's disease and Lewy body dementia, p25alpha was detectable in the neuronal Lewy body inclusions along with alpha-synuclein. The localization in alpha-synuclein-containing inclusions was verified biochemically by immunological detection in Lewy body inclusions purified from Lewy body dementia tissue and glial cytoplasmic inclusions purified from tissue from multiple systems atrophy. We suggest that p25alpha plays a pro-aggregatory role in the common neurodegenerative disorders hall-marked by alpha-synuclein aggregates.

Amino Acid Sequence↗

PubMed1998

Contrasting actions of pressor agents in severe autonomic failure.

BACKGROUND: Orthostatic hypotension is the most disabling symptom of autonomic failure. The choice of a pressor agent is largely empiric, and it would be of great value to define predictors of a response. PATIENTS AND METHODS: In 35 patients with severe orthostatic hypotension due to multiple system atrophy or pure autonomic failure, we determined the effect on seated systolic blood pressure (SBP) of placebo, phenylpropanolamine (12.5 mg and 25 mg), yohimbine (5.4 mg), indomethacin (50 mg), ibuprofen (600 mg), caffeine (250 mg), and methylphenidate (5 mg). In a subgroup of patients, we compared the pressor effect of midodrine (5 mg) with the effect of phenylpropanolamine (12.5 mg). RESULTS: There were no significant differences in the pressor responses between patients with multiple system atrophy or pure autonomic failure. When compared with placebo, the pressor response was significant for phenylpropanolamine, yohimbine, and indomethacin. In a subgroup of patients, we confirmed that this pressor effect of phenylpropanolamine, yohimbine, and indomethacin corresponded to a significant increase in standing SBP. The pressor responses to ibuprofen, caffeine, and methylphenidate were not significantly different from placebo. Phenylpropanolamine and midodrine elicited similar pressor responses. There were no significant associations between drug response and autonomic function testing, postprandial hypotension, or plasma catecholamine levels. CONCLUSIONS: We conclude that significant increases in systolic blood pressure can be obtained in patients with orthostatic hypotension due to primary autonomic failure with phenylpropanolamine in low doses or yohimbine or indomethacin in moderate doses. The response to a pressor agent cannot be predicted by autonomic function testing or plasma catecholamines. Therefore, empiric testing with a sequence of medications, based on the risk of side effects in the individual patient and the probability of a response, is a useful approach.

Aged↗

PubMed2001

Measurement of the midbrain diameter on routine magnetic resonance imaging: a simple and accurate method of differentiating between Parkinson disease and progressive supranuclear palsy.

Anteroposterior diameters of the suprapontine midbrain, the pons, and the collicular plate were measured in 50 patients with various parkinsonian syndromes (Parkinson disease [PD] [n = 20], progressive supranuclear palsy [PSP] [n = 16], and multiple-system atrophy of striatonigral type [n = 14]) and 12 age-matched healthy control subjects by means of axial T2-weighted magnetic resonance images. While no differences in midbrain diameter were found between patients with PD (mean, 18.5 mm) and control subjects (mean, 18.2 mm), patients with PSP had significantly lower midbrain diameters (mean, 13.4 mm) than patients with PD and control subjects (P<.001), without any overlap between these 2 groups. However, midbrain diameters of patients with multiple-system atrophy were also significantly lower than those of control subjects and patients with PD, with individual values showing overlap with the PSP, PD, and control groups. Pontine and collicular plate diameters did not contribute additional information. We therefore conclude that measurement of anteroposterior diameter of the midbrain on axial T2-weighted magnetic resonance images is a reliable means to differentiate patients with PSP from those with PD and should be incorporated into the diagnostic criteria for PSP.

Aged↗

PubMed1989

The value of urethral sphincter electromyography in the differential diagnosis of parkinsonism.

A series of 54 patients presenting with parkinsonism underwent clinical assessment and urethral sphincter electromyography (EMG). After clinical assessment, 26 were thought to be suffering from probable multiple system atrophy (MSA), 15 were thought to have possible MSA and 13 were diagnosed as having probable idiopathic Parkinson's disease (IPD). Of those with probable MSA, 16 were found to have an abnormal urethral sphincter EMG. In the group with possible MSA, only 5 patients had an abnormal EMG while in the group with probable IPD, only 1 patient had an abnormal EMG. It was concluded that urethral sphincter electromyography provides a useful method of distinguishing between idiopathic Parkinson's disease and multiple system atrophy. It also provides a means of identifying those patients with parkinsonism whose incontinence may well be worsened, or in whom incontinence may develop following lower urinary tract surgery.

Aged↗

PubMed1986

The neuropathology of progressive autonomic failure of central origin (the Shy-Drager syndrome).

The neuropathological features of the "Shy-Drager syndrome" have, in the past, been unsettled. The position was recently clarified by Oppenheimer who reviewed the 51 reported patients with progressive autonomic failure in whom neuropathological findings were given. He divided these cases into two groups. Group I included those with lesions of the pigmented nuclei of the brain stem which contained Lewy bodies. These he further subdivided into subgroups IA or IB according to whether or not the patient showed clinical evidence of Parkinson's disease in addition to the common denominator of orthostatic hypotension. In group II he placed those patients in whom multiple system atrophy was found at necropsy. These were the majority. Loss of neurons from the intermediolateral columns of the thoracic spinal cord, thought to be the cause of the postural hypotension, was present in all cases. To illustrate the new classification the necropsy findings in 3 patients taken from the files of the Royal Perth Hospital are described. One of these showed the lesions of Parkinson's disease with Lewy bodies, and thus conformed to Oppenheimer's type IA. The two other patients showed multiple system atrophy and thus belonged to Oppenheimer's type II. All three showed loss of neurons in the intermediolateral columns of the thoracic spinal cord. We believe that Oppenheimer's classification of progressive orthostatic hypotension improves the clinicopathological understanding of the syndrome and is thus useful as well as informative to the practising neurologist.

Aged↗

PubMed1993

3H-spiperone binding to lymphocytes fails in the differential diagnosis of de novo Parkinson syndromes.

In order to investigate the diagnostic value of 3H-spiperone binding capacity to lymphocytes in the differential diagnosis of de novo Parkinson's disease (idiopathic Parkinson syndrome, PD), we performed a double blind prospective study of spiperone binding capacity of 123 patients and 23 healthy control persons, belonging to different diagnostic groups (PD, Parkinsonian syndrome due to vascular lesions, multiple system atrophy [MSA], essential tremor). Diagnoses were based on medical history, clinical examination, CT or MRI scan, acute response to dopamimetic drugs, one year follow up, and long term response to L-DOPA treatment. Spiperone binding was assayed using ten different concentrations (0.03-3 nmol) in absence or presence of 1 mumol (+)-butaclamol to determine nonspecific binding. There was no significant difference in spiperone binding between patients with PD not treated with L-DOPA, and patients with other basal ganglia disorders including parkinsonian syndrome due to vascular lesions, multiple system atrophy, or progressive supranuclear palsy, and age matched controls. Binding was significantly higher in parkinsonian patients with PD treated with L-DOPA and patients with essential tremor. It is concluded that at present 3H-spiperone binding gives no further information in the differential diagnosis of de novo Parkinson's disease.

Adult↗

PubMed2002

Catechol-o-methyltransferase and blood pressure in humans.

BACKGROUND: Whether catechol-O-methyltransferase (COMT), the enzyme that metabolizes extraneuronal norepinephrine, contributes to blood pressure regulation in humans is unknown. METHODS AND RESULTS: We studied incremental doses of the COMT inhibitor entacapone, the sympathetic stimulant yohimbine, and placebo in 7 patients with multiple system atrophy (Shy Drager syndrome). We selected these unique subjects because norepinephrine exerts an exaggerated increase in blood pressure in these patients. Autonomic regulation was characterized with intravenous phenylephrine, nitroprusside, and trimethaphan. Patients were extremely hypersensitive to phenylephrine and nitroprusside. Trimethaphan elicited a profound depressor response. Phenylephrine sensitivity increased only slightly during ganglionic blockade. Entacapone increased systolic blood pressure dose-dependently; however, the pressor response to yohimbine was approximately 3.5 times greater than the maximal response to entacapone. CONCLUSIONS: COMT inhibition elicits a moderate, dose-dependent pressor response in the setting of severely impaired baroreflex buffering. Patients with multiple system atrophy allow for the characterization of subtle manipulations of norepinephrine turnover and blood pressure regulation in small numbers of subjects.

Baroreflex↗

PubMed2006

Pathological changes in dopaminergic nerve cells of the substantia nigra and olfactory bulb in mice transgenic for truncated human alpha-synuclein(1-120): implications for Lewy body disorders.

Dysfunction of the 140 aa protein alpha-synuclein plays a central role in Lewy body disorders, including Parkinson's disease, as well as in multiple system atrophy. Here, we show that the expression of truncated human alpha-synuclein(1-120), driven by the rat tyrosine hydroxylase promoter on a mouse alpha-synuclein null background, leads to the formation of pathological inclusions in the substantia nigra and olfactory bulb and to a reduction in striatal dopamine levels. At the behavioral level, the transgenic mice showed a progressive reduction in spontaneous locomotion and an increased response to amphetamine. These findings suggest that the C-terminal of alpha-synuclein is an important regulator of aggregation in vivo and will help to understand the mechanisms underlying the pathogenesis of Lewy body disorders and multiple system atrophy.

Animals↗

PubMed1993

[Spinocerebellar degeneration in Japan--the feature from an epidemiological study].

A nationwide epidemiological study on spinocerebellar degeneration (SCD) including multiple system atrophy was performed in Japan from 1988 to 1989. The national prevalence rate of SCD was estimated to be 4.53/100,000 in 1987. The percentage of patients with each subtype of SCD was; olivopontocerebellar atrophy (OPCA) 34.4%, Menzel type of hereditary cerebellar ataxia (MHCA) 12.6%, Holmes type of hereditary cerebellar ataxia (HHCA) 7.5%, Shy-Drager syndrome (SDS) 7.0%, hereditary spastic paraplegia (HSP) 3.9%, dentatorubro-pallidoluysian atrophy (DRPLA) 2.5%, Friedreich ataxia (FA) 2.4%, Joseph disease (JD) 2.0%, and striatonigral degeneration (SND) 1.5% in decreasing order. In Japan, compared to European countries, non-hereditary types seemed to be commoner than hereditary types. OPCA was the most common disorder, but FA which is the most common disorder in European countries was found to be rare in Japan. We grouped the SCD on the basis of common pathological lesions, and compared the clinical features in the same group according to the severity stages. Similarity and differences in non-hereditary cerebellar form (LCCA, HHCA), multiple system atrophy (OPCA, SDS, SND), hereditary cerebello-brainstem form (MHCA, JD, DRPLA), and hereditary spinal from (FA, HSP) were elucidated. As to the functional status in SCD, there was a significant association between the severity of illness and the level of independence in each item of ADL, and also between poorer functional prognosis and presence of extrapyramidal and autonomic signs.

Humans↗

PubMed2000

[Clinical diagnostic criteria in Parkinson's disease and parkinsonian syndromes: review of the literature].

This paper reviews the validity of clinical diagnostic criteria developed for Parkinson's disease and parkinsonian syndromes. Proposed criteria are predominantly empirical. There are only a few studies with neuropathological verifications. For Parkinson's disease and Progressive Supranuclear Palsy clinicopathological studies have been performed and led to pathologically based criteria. In this context, the specificity and sensitivity of clinical criteria could be assessed. Reliability however has seldom been tested. In contrast, the proposed criteria for the clinical diagnosis of Multiple System Atrophy and Corticobasal atrophy have not been pathologically evaluated.

Humans↗

PubMed2000

Fiber diffraction of synthetic alpha-synuclein filaments shows amyloid-like cross-beta conformation.

Filamentous inclusions made of alpha-synuclein constitute the defining neuropathological characteristic of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Rare familial cases of Parkinson's disease are associated with mutations A53T and A30P in alpha-synuclein. We report here the assembly properties and secondary structure characteristics of recombinant alpha-synuclein. Carboxy-terminally truncated human alpha-synuclein (1-87) and (1-120) showed the fastest rates of assembly, followed by human A53T alpha-synuclein, and rat and zebra finch alpha-synuclein. Wild-type human alpha-synuclein and the A30P mutant showed slower rates of assembly. Upon shaking, filaments formed within 48 h at 37 degrees C. The related proteins beta- and gamma-synuclein only assembled after several weeks of incubation. Synthetic human alpha-synuclein filaments were decorated by an antibody directed against the carboxy-terminal 10 amino acids of alpha-synuclein, as were filaments extracted from dementia with Lewy bodies and multiple system atrophy brains. Circular dichroism spectroscopy indicated that alpha-synuclein undergoes a conformational change from random coil to beta-sheet structure during assembly. X-ray diffraction and electron diffraction of the alpha-synuclein assemblies showed a cross-beta conformation characteristic of amyloid.

Amyloid↗