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Results for “Multiple System Atrophy”

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PubMed2003

Psychoneurological applications of endoscopic sympathetic blocks (ESB).

In addition to more widely and longer known indications of ETS, various neurological disorders and psychologically stressful situations in their worst expressions might be alleviated by the reversible ESB procedure. The patients with social phobia, especially those who have also blushing and/or stage fright type of heart racing, benefit from the ESB. The disturbances of the sympathetic nervous system, e. g. in Parkinson's disease and multiple system atrophy might be alleviated with sympathetic block, especially the extrapyramidal symptoms in these diseases. In migraine, sympathetic surgery has been noted to give some help. The unilateral left-sided block has been effective in long QT-syndrome type arrhythmias. In schizophrenia, the phobic, paranoic or confusional reactions have been tentatively treated by the sympathetic block.

Anxiety Disorders↗

PubMed2004

Adrenergic responsiveness of adipose tissue lipolysis in autonomic failure.

The sympathetic nervous system mobilizes lipids from adipose tissue through stimulation of beta-adrenergic receptors. The increase in lipid supply augments lipid oxidation. Patients with autonomic failure provide a unique opportunity to further elucidate the role of the adrenergic system in adipose tissue metabolism. In 4 patients with severe pure autonomic failure (PAF), in 3 multiple system atrophy patients (MSA), and in 16 healthy young controls, we inserted a microdialysis catheter in abdominal adipose tissue. The catheter was perfused with incremental concentrations of the nonselective beta-adrenoreceptor agonist isoproterenol. Dialysate glucose, lactate, and glycerol were measured to assess glucose supply, glycolysis, and lipolysis, respectively. Basal dialysate glycerol concentrations were 84 +/- 28 microM in PAF and 130 +/- 64 microM in MSA patients. The increase in dialysate glycerol with isoproterenol was identical in PAF and in MSA patients. We found an almost complete overlap in dialysate glycerol concentrations during isoproterenol stimulation between PAF and MSA patients and healthy young control subjects. Our findings suggest that adipose tissue metabolism is remarkably well preserved in patients with chronic sympathetic denervation, both at rest and during local adrenergic stimulation. We propose that beta-adrenoreceptor upregulation is compensated by a desensitization of post receptor mechanisms or by an upregulation of antilipolytic pathways.

Adipose Tissue↗

PubMed2004

Clinical pharmacokinetics of the norepinephrine precursor L-threo-DOPS in primary chronic autonomic failure.

BACKGROUND: Oral L-threo-3,4-dihydroxyphenylserine (L-DOPS), a synthetic catechol amino acid, increases standing blood pressure and improves standing ability in patients with neurogenic orthostatic hypotension, by conversion of L-DOPS to norepinephrine (NE) outside the brain. This study assessed the pharmacokinetics of L-DOPS, NE, and dihydroxyphenylglycol (DHPG), the main neuronal metabolite of NE, in patients with primary chronic autonomic failure from pure autonomic failure (PAF) or multiple system atrophy (MSA). METHODS: In 5 MSA and 4 PAF patients, antecubital venous blood was drawn during supine rest and plasma levels of catechols measured at various times for 48 hours after a single oral dose of 400 mg of L-DOPS. RESULTS: Plasma L-DOPS peaked at 1.9 microg/ml (9 micromol/L) about 3 hours after drug administration, followed by a monoexponential decline with a half-time of 2-3 hours in both patient groups. Plasma NE and DHPG also peaked at about 3 hours, but at much lower concentrations (4 and 42 nmol/L). Compared to the MSA group, the PAF group had a smaller calculated volume of distribution of L-DOPS and up to 10-fold lower plasma NE levels at all time points. Plasma NE was above baseline in MSA even at 48 hours after L-DOPS. CONCLUSIONS: The relatively long half-time for disappearance of L-DOPS compared to that of NE explains their very different attained plasma concentrations. The similar NE and DHPG responses in PAF and MSA suggests production of NE from LDOPS mainly in non-neuronal cells. Persistent elevation of plasma NE in MSA suggests residual release of NE from sympathetic nerves.

Aged↗

PubMed2006

Neuroendocrine and behavioural responses to CO2 inhalation in central versus peripheral autonomic failure.

Multiple system atrophy (MSA) and pure autonomic failure (PAF) represent distinct pathological models of autonomic failure in humans. We have investigated the neuroendocrine, behavioural and autonomic cardiovascular responses to the 35% CO2 challenge. Nine patients with MSA, nine with PAF and five control subjects received a single breath of 35% CO2. Peripheral autonomic failure (i.e., PAF) was associated with significantly lower resting noradrenaline levels. All groups demonstrated a significant pressor response to CO2. In controls, the mean pressor response was +60.2 mm Hg, which was significantly smaller in both the PAF (+26.8 mm Hg, P < 0.01) and MSA (+18.3 mm Hg, P < 0.001) patients. In addition, the onset of the response was significantly delayed in both MSA (140.2 s) and PAF (154.2 s) patients compared with controls (32.4 s, P = 0.04 and P = 0.03, respectively). Noradrenaline levels increased only in controls. Central autonomic impairment (i.e., MSA) was associated with lower cortisol release (+8.8% in MSA compared with +35.2% in control and +23.7% in PAF) and fewer somatic symptoms of emotional arousal. Both MSA and PAF exhibit marked sympathetic autonomic impairment, however, residual (albeit differing) sympathetic pathways can still maintain a partial cardiovascular response. A central autonomic lesion, however, also appears to be associated with blunting of both cortisol and emotional responses to this stress paradigm.

Aged↗

PubMed2004

Review of rapid eye movement behavior sleep disorders.

The spectrum of rapid eye movement behavior disorders (RBD) spans various age groups, with the greatest prevalence in elderly men. Major diagnostic features include harmful or potentially harmful sleep behaviors that disrupt sleep continuity and dream enactment during rapid eye movement sleep. In RBD patients, the polysomnogram during rapid eye movement sleep demonstrates excessive augmentation of chin electromyogram or excessive chin or limb phasic electromyogram twitching. RBD may be associated with various neurodegenerative disorders, such as multiple system atrophy, Parkinson's disease, and dementia with Lewy bodies. Other co-morbid conditions may include narcolepsy, agrypnia excitata, sleepwalking, and sleep terrors. RBD is hypothesized to be caused by primary dysfunction of the pedunculo-pontine nucleus or other key brainstem structures associated with basal ganglia pathology or, alternatively, from abnormal afferent signals in the basal ganglia leading to dysfunction in the midbrain extrapyramidal area/ pedunculo-pontine nucleus regions.

Adolescent↗

PubMed2006

Mechanisms and models of alpha-synuclein-related neurodegeneration.

Expression of the Parkinson's disease-associated protein alpha-synuclein causes formation of aggregates and cytotoxicity in a great diversity of transgenic model organisms, in the case of Drosophila melanogaster affecting specific dopaminergic neuron clusters. The relative contribution of alpha-synuclein misfolding and phosphorylation for neurodegeneration was elucidated in these systems. In transgenic mice, typical neuropathologic inclusions formed concomitant with behavioral deficits, reminiscent of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Neuronal degeneration was cell-autonomous in the Lewy body disease models, whereas gliotic changes accompanied neurodegeneration caused by (oligodendro)glial cytoplasmic inclusions. These recent findings provided major insights into the molecular mechanisms of alpha-synucleinopathies.

Animals↗

PubMed2006

Management of hypertension in the setting of autonomic dysfunction.

Supine hypertension is a common finding in patients with autonomic failure; it is associated with end-organ damage and produces nighttime pressure diuresis with worsening of orthostatic hypotension. During the daytime, it is best treated by avoiding the supine posture. At night, simple measures such as raising the head of the bed by 6 to 9 inches can be effective, but most patients require pharmacologic treatment. Transdermal nitroglycerin (0.1 to 0.2 mg/h) or nifedipine (30 mg, orally) has proved to be effective. Hydralazine and minoxidil are usually less effective but may be useful in a given patient. One key therapeutic concept is the hypersensitivity of these patients to depressor agents, requiring a careful titration of the doses on an individual basis. For those patients with proven residual sympathetic tone, as in multiple system atrophy, central sympatholytics such as clonidine may provide an alternative.

Journal Article↗

PubMed1991

Noradrenergic nerve fibers of the rectal mucosa in autonomic disorders: comparison of histochemical study with clinical severity and changes in plasma noradrenaline induced by standing.

A histochemical study was carried out on the rectal mucosae biopsied from 20 patients with autonomic dysfunctions and 13 controls using a catecholamine fluorescent staining method, and the rectal noradrenergic nerve fiber lesions were compared with the severity of autonomic symptoms and disturbance of plasma noradrenaline increase in response to standing in 17 patients. In 9 patients with type I familial amyloid polyneuropathy and 1 with acute pandysautonomia, the number of fluorescent nerve fibers was greatly reduced, and the degree of depletion correlated well with the other 2 parameters showing the severity of autonomic dysfunction. In contrast, rectal noradrenergic nerve fibers were normally preserved in 10 patients with multiple system atrophy, although they suffered from severe autonomic symptoms with poor noradrenaline response to the postural loading. It is concluded that noradrenergic nerve fiber lesions in the biopsied rectal mucosa may represent the systemic involvement of sympathetic post-ganglionic nerves.

Adult↗

PubMed1993

Cerebrospinal fluid 28-kDa calbindin-D as a possible marker for Purkinje cell damage.

To examine the clinical value of 28-kDa calbindin-D (CaBP) in cerebrospinal fluid (CSF) as a marker for the damage to Purkinje cells, we measured CSF CaBP levels using an enzyme immunoassay method in 107 patients with cerebellar and other neurological diseases, and 26 controls. The mean CaBP level was markedly elevated in patients with cerebellar diseases, and the elevation of CaBP level was more frequent in the diseases involving Purkinje cells, such as multiple system atrophy (MSA) and subacute cerebellar degeneration in association with lung cancer. Further, in MSA patients, the CaBP levels decreased with duration of illness. The mean levels of CaBP were also elevated in some of the other diseases. We conclude that the elevations of CaBP levels are not specific for cerebellar diseases, but CSF CaBP may be a useful marker for examining the Purkinje cell involvement in cerebellar diseases.

Adolescent↗

PubMed1995

Sympathetic skin responses evoked by magnetic stimulation of the neck.

We studied sympathetic skin responses (SSRs) following magnetic stimulation of the neck in 40 normal subjects and 54 patients with neurological diseases and active sweat gland densities (ASGDs) at the foot induced by pilocarpine in 39 patients. SSRs at the hand following magnetic stimulation showed the lowest coefficients of variability of the latencies and amplitudes in eight consecutive responses compared with SSRs following other types of stimuli (electrical and auditory stimulation, and deep inspiration) in 12 normal subjects. Fourteen of 38 patients with neuropathies (37%) showed the presence of SSRs after magnetic stimulation, but not after median nerve stimulation, although SSRs to magnetic stimulation corresponded with those to nerve stimulation in all patients with multiple sclerosis or multiple system atrophy. These results suggest that the absence of SSRs after nerve stimulation in patients with neuropathies may be due to abnormalities of the peripheral sensory afferent fibers. ASGDs significantly correlated with SSRs at the foot following magnetic stimulation, but not with those following nerve stimulation in patients with neuropathies. Magnetic stimulation of the neck is the highly reproducible method of evoking SSRs because this technique is able to produce strong sensory afferent inputs proximally. Furthermore, SSRs following magnetic stimulation, little influenced by sensory afferent fiber involvement, are very useful for evaluating the postganglionic sympathetic function in patients with neuropathies.

Action Potentials↗

PubMed1988

Relationship between urinary excretion of homovanillic acid and norepinephrine metabolites in normal subjects and patients with orthostatic hypotension.

Patients with neurogenic orthostatic hypotension due to multiple system atrophy (MSA) or pure autonomic failure (PAF) excrete lower amounts of homovanillic acid (HVA) than do normal subjects. There is a highly significant correlation between the rates of excretion of HVA and norepinephrine metabolites. The regression line relating excretion of the dopamine and norepinephrine metabolites suggests that about one third of dopamine formed in noradrenergic neurons is converted to norepinephrine and the remainder metabolized, mainly to HVA. About one fourth of urinary HVA appears to be derived from a source independent of norepinephrine; this source is probably brain dopaminergic neurons.

Atrophy↗

PubMed1992

Growth hormone response to clonidine in central and peripheral primary autonomic failure.

Patients with primary autonomic failure may have either pure autonomic failure (PAF) or multiple system atrophy (MSA) in which there is additional neurological involvement. Distinction between PAF and MSA at an early stage is important because a wide range of complications is associated with MSA, which has a poor response to drug therapy and a less favourable prognosis. We have investigated the growth hormone (GH) releasing effects of clonidine in patients with PAF and MSA to see whether this hormonal response could serve as a neuroendocrine marker to distinguish between the groups. Age-matched normal subjects were studied as controls. Both groups of patients had severe postural hypotension due to primary sympathetic failure of presumed central origin in MSA and peripheral origin in PAF. After clonidine, plasma GH concentrations increased in controls and PAF, with no change in MSA. Changes in plasma glucose and insulin concentrations were similar in all groups. Clonidine, therefore, stimulates growth hormone release in PAF but not MSA and may serve as a neuroendocrine marker in differentiating patients with MSA and a central autonomic defect from those with PAF with a peripheral defect.

Adult↗

PubMedDate not supplied

Clinical studies of autonomic function and dysfunction.

A discussion of progressive autonomic failure in man. This is one of the few neurological diseases disrupting cardiovascular function. Both central and peripheral pathways are involved. Means of diagnosing defects in autonomic reactions are described. Abnormalities in responses due to multiple system atrophy (MSA) are discussed most extensively.

Afferent Pathways↗

PubMed1995

A scintigraphical qualitative analysis of peripheral vascular sympathetic function with meta-[123I]iodobenzylguanidine in neurological patients with autonomic failure.

In order to assess qualitatively the sympathetic functions of the peripheral vessels, we performed a scintigraphical study of the entire body with meta-[123I]iodobenzylguanidine (MIBG) in 13 patients with autonomic failure and 11 healthy subjects as control. The patients comprised seven with multiple system atrophy (MSA), two with pure autonomic failure (PAF), three with Parkinson's disease with autonomic failure (PD with AF) and one with familial amyloid polyneuropathy (FAP). No clinical evidence of vascular disease was noted in any of the patients and the control subjects. We investigated their autonomic functions using the head up tilt test as well as norepinephrine and isoproterenol infusion tests. We found that: (i) All of the control subjects showed satisfactory MIBG uptake; (ii) all of the patients with PAF and FAP, most of whom had postganglionic sympathetic lesions, showed supersensitivity and low MIBG uptake; (iii) almost all the patients with MSA, who were considered to have mainly preganglionic sympathetic lesions, showed supersensitivity and diminished MIBG uptake, although the patients with olivopontocerebellar atrophy showed supersensitivity but not diminished MIBG uptake. In conclusion, these results suggest that peripheral vascular scintigraphy using MIBG is useful in detecting peripheral adrenergic dysfunction.

3-Iodobenzylguanidine↗

PubMed1996

Transneuronal degeneration in substantia nigra pars reticulata following striatal excitotoxic injury in adult rat: time-course, distribution, and morphology of cell death.

Previous studies have demonstrated neuronal loss in the substantia nigra pars reticulata following excitotoxic injury to the striatum of adult rats, and have considered this to be an anterograde transneuronal effect. However, the mode and temporal pattern of cell death in this model are unknown. We injected ibotenate into the striatum of adult rats and performed Nissl and silver staining of the substantial nigra, the globus pallidus and the entopeduncular nucleus at multiple times up to postlesion day 28. Silver-stained degenerating cells were identified in the substantia nigra pars reticulata at days 3-14 after the lesion, with maximal occurrence at day 3. Degenerating cells and fibers were preferentially distributed in the central region of the substantia nigra pars reticulata. At the cellular level, degenerating cells, frequently demonstrating morphological characteristics of neurons, showed intense silver staining of the nucleus and punctate staining of the cytoplasm. Apoptosis was not observed. In situ end-labeling confirmed the non-apoptotic nature of the cell death. There was no secondary cellular degeneration in other striatal targets, including the globus pallidus, substantia nigra pars compacta or entopeduncular nucleus. Double staining with silver and tyrosine hydroxylase immunohistochemistry disclosed degenerating cells within the tyrosine hydroxylase-positive ventral tier in the substantia nigra pars reticulata, but in no instance was there double staining within a single cell. Our results demonstrate that secondary neuronal degeneration occurs within the substantia nigra pars reticulata within a few days following excitotoxic injury to the striatum of adult rats. The cell death is non-apoptotic, unlike that occurring in the substantia nigra of neonatal rats following similar striatal lesion. This mode of transneuronal cell death may be relevant to human diseases, such as Huntington's disease and the multiple system atrophies, in which, in addition to the major striatal neuronal loss, there is considerable loss of neurons in the substantia nigra pars reticulata.

Animals↗

PubMed2006

Outcomes of a computer-based cognitive rehabilitation program on Alzheimer's disease patients compared with those on patients affected by mild cognitive impairment.

The aim of the present study is to evaluate the outcomes of a computer-based cognitive training on patients affected by Alzheimer's disease (AD) compared with the outcomes on patients affected by mild cognitive impairment (MCI), multiple system atrophy (MSA). Ten AD patients aged 74.1+/-5.6 years, with mini-mental state examination (MMSE) score at baseline of 23.9+/-2.4, and 10 MCI patients aged 70.6+/-6.0 years, with MMSE score of 28.0+/-1.4, attending our day-hospital of neurorehabilitation were selected for the study. Three MSA patients aged 69.0+/-9.5 years, MMSE scores 26.7+/-2.3 were selected from the same setting in order to have a different control group. Each patient attended two training programs and was evaluated according to cognitive and non-cognitive functions at baseline at the end of the second training program. The AD group showed a significant MMSE score improvement (p=0.010). On the contrary, MMSE scores at baseline and at follow-up remained quite stable in the other two groups. AD patients also showed significant improvement in the areas of verbal production (p=0.036) and executive functions (p=0.050). MCI patients significantly improved in behavioral memory (p=0.017; p=0.011). No significant improvement was observed in MSA group. Our data seem to indicate that the same individualized rehabilitative intervention could have different effects according to patient's diagnosis. MCI and AD patients had significant improvements in global cognitive status and/or in specific cognitive areas. On the contrary, MSA patients did not benefit at all.

Aged↗

PubMed2004

TPPP/p25: from unfolded protein to misfolding disease: prediction and experiments.

TPPP/p25, the first representative of a new protein family, identified as a brain-specific unfolded protein induces aberrant microtubule assemblies in vitro, suppresses mitosis in Drosophila embryo and is accumulated in inclusion bodies of human pathological brain tissues. In this paper, we present prediction and additional experimental data that validate TPPP/p25 to be a new member of the "intrinsically unstructured" protein family. The comparison of these characteristics with that of alpha-synuclein and tau, involved also in neurodegenerative diseases, suggested that although the primary sequences of these proteins are entirely different, there are similarities in their well-defined unstructured segments interrupted by "stabilization centres", phosphorylation and tubulin binding motives. SK-N-MC neuroblastoma cells were transfected with pEGFP-TPPP/p25 construct and a stable clone denoted K4 was selected and used to establish the effect of this unstructured protein on the energy state/metabolism of the cells. Our data by analyzing the mitochondrial membrane polarization by fluorescence microscopy revealed that the high-energy phosphate production in K4 clone is not damaged by the TPPP/p25 expression. Biochemical analysis with cell homogenates provided quantitative data that the ATP level increased 1.5-fold and the activities of hexokinase, glucosephosphate isomerase, phosphofructokinase, triosephosphate isomerase and glyceraldehyde-3-phosphate dehydrogenase were 1.2 to 2.0-fold higher in K4 as compared to the control. Our modelling using these data and rate equations of the individual enzymes suggests that the TPPP/p25 expression stimulates glucose metabolism. At pathological conditions TPPP/p25 is localized in inclusion bodies in multiple system atrophy, it tightly co-localizes with alpha-synuclein, partially with tubulin and not with vimentin. The previous and the present studies obtained with immunohistochemistry with pathological human brain tissues rendered it possible to classify among pathological inclusions on the basis of immunolabelling of TPPP/p25, and suggest this protein to be a potential linkage between Parkinson's and Alzheimer's diseases.

Brain↗

PubMed2004

Accumulation of beta- and gamma-synucleins in the ubiquitin carboxyl-terminal hydrolase L1-deficient gad mouse.

The synuclein family includes three isoforms, termed alpha, beta and gamma. alpha-Synuclein accumulates in various pathological lesions resulting from neurodegenerative disorders including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy. However, neither beta- nor gamma-synuclein has been detected in Lewy bodies, and thus it is unclear whether these isoforms contribute to neurological pathology. In the present study, we used immunohistochemistry to demonstrate accelerated accumulation of beta- and gamma-synucleins in axonal spheroids in gracile axonal dystrophy (gad) mice, which do not express ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1). gamma-Synuclein immunoreactivity in the spheroids appeared in the gracile nucleus at 3 weeks of age and was maintained until 32 weeks. beta-Synuclein immunoreactivity appeared in spheroids around 12 weeks of age. In contrast, alpha-synuclein immunoreactivity was barely detectable in spheroids. Immunoreactivity for synaptophysin and ubiquitin were either faint or undetectable in spheroids. Given that UCH-L1 deficiency results in axonal degeneration and spheroid formation, our findings suggest that beta- and gamma-synuclein participate in the pathogenesis of axonal swelling in gad mice.

Amino Acid Sequence↗