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Results for “Multiple System Atrophy”

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PubMed2000

What clinical features are most useful to distinguish definite multiple system atrophy from Parkinson's disease?

OBJECTIVES: Few studies have attempted to identify what premortem features best differentiate multiple system atrophy (MSA) from Parkinson's disease (PD). These studies are limited by small sample size, clinical heterogeneity, or lack of postmortem validation. We evaluated the sensitivity and specificity of different clinical features in distinguishing pathologically established MSA from PD. METHODS: One hundred consecutive cases of pathologically confirmed PD and 38 cases of pathologically confirmed MSA in one Parkinson's disease brain bank were included. All cases had their clinical notes reviewed by one observer (AH). Clinical features were divided into two groups: those occurring up to 5 years after onset of disease and those occurring up to death. Statistical analysis comprised multivariate logistic regression analysis to choose and weight key variables for the optimum predictive model. RESULTS: The selected early features and their weightings were: autonomic features (2), poor initial levodopa response (2), early motor fluctuations (2), and initial rigidity (2). A cut off of 4 or more on the ROC curve resulted in a sensitivity of 87.1% and specificity of 70.5%. A better predictive model occurred if the following features up to death were included: poor response to levodopa (2), autonomic features (2), speech or bulbar dysfunction (3), absence of dementia (2), absence of levodopa induced confusion (4), and falls (4). The resulting ROC curve based on individual scores showed a best cut off score of at least 11 of 17 (sensitivity 90.3%, specificity 92.6%). CONCLUSIONS: Predictive models may help differentiate MSA and PD premortem. Hitherto poorly recognised features, suggestive of MSA, included preserved cognitive function and absence of psychiatric effects from antiparkinsonian medication. Diagnostic accuracy was higher in those models taking into account all clinical features occurring up to death. Further studies need to be based on new incident cohorts of parkinsonian patients with subsequent neuropathological evaluation.

Adult↗
PubMed2002

Longitudinal MRI study of multiple system atrophy - when do the findings appear, and what is the course?

Several investigators have revealed features of multiple system atrophy (MSA) by magnetic resonance imaging (MRI). For use in clinical diagnosis, we determined the exact time when two main features of pontine and putaminal intensity changes appeared. Furthermore, in order to reveal the course from when the disorder first appeared and how it spread, we also investigated the course of MRI findings and differences between clinical subtypes. The cranial MRI of 42 patients with MSA were longitudinally studied including comments on the so called "cross sign" of pontine T2 high intensity, which was divided into 6 stages, and also on the linear T2 high intensity of the dorsolateral side of the putamen ("putaminal slit") which was divided into 4 stages. Patients were classified as 16 MSA-C, 7 autonomic dominant type (MSA-A), and 19 MSA-P. The age at onset ranged from 41 to 74 years (mean, 55 +/- 9). The duration of the disease in the MRI study ranged from 1 to 24 years. The pontine "cross sign" was completed (shows Cross, stage IV) earlier in MSA-C mainly before 5 years, later in MSA-P and even much later in MSA-A. Regarding the "putaminal slit", MSA-P shows earlier bilateral changes (stage II), mostly before 3 years, compared with MSA-C, which requires 4 years to reveal even a unilateral change (stage I), or MSA-A which requires even more time. MRI findings showed a tendency to relate to clinical findings, since MSA-C exhibits "cross sign" completion earlier than bilateral "putaminal slit"; however, MSA-P shows bilateral "putaminal slit" earlier than "cross sign", and MSA-A requires much more time to show both. Clinically, MSA-C, MSA-A, or MSA-P showed different MRI courses so that three subtypes could be defined also with MRI findings. Therefore these observations are useful not only for diagnosis of MSA itself, but also to distinguish clinical subtypes (MSA-C, MSA-A, or MSA-P) which have different rates of lesion progression.

Adult↗
PubMed1998

Cloning and mapping of ZNF231, a novel brain-specific gene encoding neuronal double zinc finger protein whose expression is enhanced in a neurodegenerative disorder, multiple system atrophy (MSA).

A novel brain-specific gene, neuronal double zinc finger protein (ZNF231), was cloned and mapped. We used the high-density cDNA filter method to analyze the gene-expression profile in brains with multiple system atrophy (MSA). MSA is a sporadic progressive neurodegenerative disease characterized clinically by cerebellar symptoms, parkinsonism, autonomic dysfunction, or their various combinations, but its pathogenesis has yet to be clarified. In total, 8300 cDNA clones were screened, and a novel gene, ZNF231, was identified, whose expression was elevated in cerebella of patients with MSA. Its transcript is approximately 16 kb long and encodes an open reading frame of 3926 amino acid residues that has several interesting motifs; two glycine-proline dipeptide repeats (aa 22-32 and aa 61-74), a pair of homologous C8 double zinc finger motifs (aa 169-226 and aa 465-521), a leucine zipper motif (aa 561-582), a SH3 domain-binding motif (aa 825-831), two nuclear targeting signals (aa 1011-1028 and aa 1071-1091), two glutamine-rich domains (aa 2428-2473 and aa 3775-3804), and a histidine-rich domain (aa 3597-3682). These features suggest that the new gene encodes a nuclear protein or transcription regulator. Northern blot and RT-PCR analyses showed that its expression is specific to the brain and apparently restricted to the neurons. Elevation of ZNF231 expression may be involved in the pathogenesis of multiple system atrophy. The gene for ZNF231 is located on chromosome 3p21.

Amino Acid Sequence↗
PubMed1998

Myelin degeneration in multiple system atrophy detected by unique antibodies.

A rabbit antiserum (anti-EP), induced against a synthetic peptide corresponding to residues 68 to 86 of guinea pig myelin basic protein, powerfully immunostained abnormal-appearing oligodendrocytic processes and cell bodies in demyelinating areas associated with multiple system atrophy (MSA). However, as we reported previously, the antiserum, which is highly specific for the sequence QDENPVV corresponding to human myelin basic protein residues 82 to 88, failed to recognize any structures in normal human brain. QD-9, a mouse monoclonal antibody raised against human myelin basic protein residues 69 to 88, which also recognizes specifically the epitope QDENPVV, gave the same results as did anti-EP. The unusual epitope recognized by anti-EP/QD-9 antibodies appears to be accessible in areas of myelin degeneration, and the antibodies have been shown to detect such areas in multiple sclerosis and infarcted brains. These antibodies detect myelin degeneration more widely than previous conventional methods. The present study emphasizes the importance of myelin degeneration in the pathogenesis of multiple system atrophy.

Aged↗
PubMed1996

Sympathetic skin response and R-R interval variability in multiple system atrophy and idiopathic Parkinson's disease.

We compared autonomic function in patients with multiple system atrophy (MSA) or with idiopathic Parkinson's disease (IPD) by measuring sympathetic skin response (SSR) and R-R interval variability (RRIV). SSR was investigated in 26 patients (13 with MSA and 13 patients with IPD). RRIV during deep breathing, Valsalva maneuver, and on standing was investigated in 20 patients (nine with MSA and 11 with IPD). MSA and IPD patients had similar age, illness duration, and therapy. Abnormal SSR was more frequent in MSA (69%) than in IPD (7.7%; x2, 10.4; p < 0.002). RRIV during deep breathing and the Valsalva maneuver was lower in MSA than in IPD (p = 0.02). RRIV during standing up was not significantly different in IPD and MSA. These differences between MSA and IPD may be due to more severe and widespread autonomic disturbance in MSA, related to more severe neuropathologic involvement of the autonomic nervous system. SSR and RRIV may aid in the differential diagnosis of parkinsonism and help to exclude from clinical trials MSA patients clinically misdiagnosed as having IPD.

Aged↗
PubMed1994

New observation on ubiquitinated neurons in the cerebral cortex of multiple system atrophy (MSA).

To investigate neuronal damage in the cerebral cortex in patients with multiple system atrophy (MSA), immunohistochemical stainings were carried out on the prefrontal cortex, the hippocampus, the precentral gyrus, the supplementary motor cortex and the occipital cortex in 6 cases of MSA and 6 controls, using antibodies against ubiquitin, tau protein and neurofilaments (BF10, RT97, 147). In MSA cases, a variable number of neuronal ubiquitinated inclusions were observed in the granule cell layer of the dentate gyrus (3/6) and the prefrontal cortex (3/6). An increased number of ubiquitinated dots-like structures were also observed in the parahippocampal gyrus of MSA cases (4/6) in comparison with controls. These results showed further evidence of neuronal damage in the cerebral cortex in MSA and strongly suggest a relationship between the cerebral cortical pathology and occasional manifestation of cognitive deficits in some MSA cases.

Atrophy↗
PubMed1996

Sleep-related breathing disorders in patients with multiple system atrophy and vocal fold palsy.

We performed sleep studies in eight patients with multiple system atrophy (MSA) and three patients with peripheral bilateral vocal fold palsy (PBVFP) and investigated stenosis of the upper airway tract during sleep in MSA patients with vocal fold palsy. Among the eight MSA patients in this study, five had definite glottic snoring and two others were suspected of having glottic snoring. Of the PBVFP patients, two had glottic snoring. Three of 11 patients died, and two of the three deaths occurred during sleep. Glottic snoring indicated a high degree of negative esophageal pressure. High negative esophageal pressure demonstrates severe narrowing of the upper airway tract. Therefore, glottic snoring should be considered a risk factor for sudden death in sleep. Repeated laryngoscopic examination is useful in evaluating the progressive process of vocal fold palsy while awake, but this examination performed only while awake is not enough to evaluate narrowing of the upper airway during sleep. Sleep studies that include the measurement of esophageal pressure can be very useful in evaluating the severity of narrowing in the upper airway tract. It is suspected that sudden nocturnal death in MSA patients is caused not only by abnormal respiration resulting from impairment of the respiratory center, but also by glottic obstruction caused by sputum or by edema of the vocal folds. We recommend treatment of respiratory disorders when loud laryngeal snoring occurs in patients with MSA, even if they do not complain of dyspnea while awake.

Adult↗
PubMed1990

Abnormal respiration and sudden death during sleep in multiple system atrophy with autonomic failure.

We studied respiration during sleep in 7 patients with multiple system atrophy and autonomic failure (MSA-AF) and 7 control subjects. Although mean respiratory rate, tidal volume, and inspiratory flow rate were statistically similar in both groups, the coefficients of variability in all were significantly greater in MSA-AF patients. Four of 5 nontracheostomized had evidence of upper airway obstruction without significant oxygen desaturation. Three of these 5 patients died suddenly during sleep. MSA-AF is associated with upper airway dysfunction and disordered central respirations which can be life threatening. Evidence of even mild obstruction during sleep should warrant tracheostomy.

Aged↗
PubMed1997

REM sleep behavior disorders in multiple system atrophy.

We report the results of clinical and polysomnographic investigations on 39 consecutive multiple system atrophy (MSA) patients. Twenty-seven patients (69%) reported nocturnal motor paroxysmal episodes related to dreams, suggesting the clinical diagnosis of REM sleep behavior disorder (RBD). In 12 of them (44%), RBD preceded the clinical onset of the disease by more than 1 year. In seven (26%), the RBD onset was concomitant with and in eight (30%) was at least 2 years after the appearance of motor or autonomic symptoms. On polysomnographic recordings, 35 of 39 MSA patients (90%) had RBD. Other polysomnographic findings included nonclinical obstructive sleep apnea in 6 patients, laryngeal stridor in 8 patients, and periodic limb movements during sleep in 10 patients. Our data show that RBD represents the most common clinical sleep manifestation and polysomnographic finding in patients with MSA. RBD can frequently herald the appearance of other MSA symptoms by years. Extended polysomnographic montages are recommended in MSA sleep studies.

Adult↗
PubMedDate not supplied

Expression of the endocytosis regulatory proteins Rab5 and Rabaptin-5 in glial cytoplasmic inclusions from brains with multiple system atrophy.

BACKGROUND: Glial cytoplasmic inclusions (GCIs) occur specifically in oligodendrocytes in brains with multiple system atrophy (MSA). Oligodendrocytes in MSA appear to be functionally altered in their nature in terms of the occurrence of GCIs and aberrant expression of various proteins such as neuron specific protein, MAP2 or pre-synaptic protein, ct-synuclein. The present study examined whether or not aberrant expression of the endocytosis regulatory proteins Rab5 and Rabaptin-5 occcur in oligodendrocytes of brains with MSA. MATERIALS AND METHODS: We examined immunohistochemically the post-mortem brain tissues from 5 patients with MSA and 5 controls. Immunohistochemistry was done using monoclonal anti-Rab5 and anti-Rabaptin-5 antibodies based on ABC method. RESULTS: We have observed Rab5 and Rabaptin-5 immunoreactivity in the neuronal somata and axons of the controls, suggesting that Rab5 and Rabaptin-5 are involved in the regulation of the endocytosis in neurons of the human central nervous system. In the brain tissues from patients with MSA, we have found Rab5 and Rabaptin-5 immunoreactivity in GCIs. CONCLUSION: Rab5, in association with Rabaptin-5, has been demonstrated in the early endosome and regulates the endocytosis. Since Rab5 and Rabaptin-5 have been immunolocalized to neurons in the human brains, we propose that oligodendrocytes may ectopically express Rab5 and Rabaptin-5 in MSA. Thus, the oligodendrocytes in MSA brains appear to be functionally significantly altered, which may be associated with the formation of GCIs in the oligodendrocytes.

Aged↗
PubMed2003

Dorfin localizes to the ubiquitylated inclusions in Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and amyotrophic lateral sclerosis.

In many neurodegenerative diseases, the cytopathological hallmark is the presence of ubiquitylated inclusions consisting of insoluble protein aggregates. Lewy bodies in Parkinson's disease and dementia with Lewy bodies disease, glial cell inclusions in multiple system atrophy, and hyaline inclusions in amyotrophic lateral sclerosis (ALS) are representative of these inclusions. The elucidation of the components of these inclusions and the mechanisms underlying inclusion formation is important in uncovering the pathogenesis of these disorders. We hypothesized that Dorfin, a perinuclearly located E3 ubiquitin ligase, participates in the formation of ubiquitylated inclusions in a wide range of neurodegenerative diseases. Here, we report that affinity-purified anti-Dorfin antibody labeled ubiquitylated inclusions of Parkinson's disease, dementia with Lewy bodies disease, multiple system atrophy, and sporadic and familial ALS. A double-immunofluorescence study revealed that Dorfin shows a distribution pattern parallel to that of ubiquitin. Furthermore, by a filter trap assay, we detected that Dorfin is present in the ubiquitylated high-molecular weight structures derived from these diseases. These results suggest that Dorfin plays a crucial role in the formation of ubiquitylated inclusions of alpha-synucleinopathy and ALS. However, because we failed to show the direct binding of alpha-synuclein with Dorfin, future investigations into the binding partner(s) of Dorfin will be needed to deepen our understanding of the pathophysiology of alpha-synucleinopathy and ALS.

Aged↗
PubMed1998

Vocal fold abductor paralysis as a solitary and fatal manifestation of multiple system atrophy.

A patient is presented who had bilateral abductor vocal fold paralysis pathologically proven to be due to multiple system atrophy (MSA) in the absence of other neurological features. MSA is a degenerative neurological condition that includes olivopontocerebellar atrophy, Shy-Drager syndrome and striatonigral degeneration. The usual predominant features of MSA are cerebellar ataxia, autonomic dysfunction and Parkinsonism. Stridor is present in over one third of patients and has been reported previously as a presenting symptom in MSA: however previously reported patients have always gone on to develop other neurological symptoms. The usual investigations of bilateral abductor vocal fold paralysis caused by MSA will not reveal the pathological process and we believe that magnetic resonance imaging (MRI) of the medulla and brain stem and autonomic function tests are probably the investigations of choice. It is a worthwhile exercise attempting to identify MSA as the cause of stridor as the prognosis is good in the medium term if appropriate support is offered.

Aged↗
PubMed2003

Preservation of branchimotor neurons of the nucleus ambiguus in multiple system atrophy.

Cholinergic neurons in the nucleus ambiguus (NA) were counted in autopsy tissue obtained from five patients with multiple system atrophy (MSA), four patients with PD, and five controls. The number of neurons in the dorsal NA was not significantly different among the three groups. Neurons in the ventrolateral portion of the NA were depleted in MSA. Laryngeal stridor cannot be explained solely by neuronal loss in the NA.

Aged↗
PubMed2004

Parkinson's disease-like presentation of multiple system atrophy with poor response to STN stimulation: a clinicopathological case report.

We report on a clinicopathological case of multiple system atrophy with good response to levodopa and subsequent development of motor complications. Because the subject complied with all the inclusion criteria (Core Assessment Program for Surgical Interventional Therapies in Parkinson's Disease), bilateral subthalamic nucleus deep brain stimulation electrodes were implanted.

Antiparkinson Agents↗
PubMed2004

Long-term effect of CPAP in the treatment of nocturnal stridor in multiple system atrophy.

The authors found that continuous positive airway pressure (CPAP) eliminated video-polysomnographic documented stridor in 13 multiple system atrophy (MSA) subjects with vocal cord abnormalities. Long-term follow-up showed high CPAP tolerance, no recurrence of stridor, no major side effects, subjective improvement in sleep quality, and that median survival time was similar to a group of 26 MSA patients without stridor. This study shows that in MSA, CPAP is an effective noninvasive long-term therapy for nocturnal stridor.

Aged↗
PubMed1998

Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies.

Alpha-synuclein forms the major component of Lewy bodies and Lewy neurites, the defining neuropathological characteristics of Parkinson's disease and dementia with Lewy bodies. Here we show that alpha-synuclein is also the major component of the filamentous inclusions of multiple system atrophy which comprises several neurodegenerative diseases with a shared filamentous pathology in nerve cells and glial cells. These findings provide an unexpected link between multiple system atrophy and Lewy body disorders and establish that alpha-synucleinopathies constitute a major class of human neurodegenerative disorder.

Adult↗