A Japanese familial ALS patient with autonomic failure and a p.Cys146Arg mutation in the gene for SOD1 (SOD1).

We describe a Japanese man with familial amyotrophic lateral sclerosis (ALS) associated with a p.Cys146Arg mutation in the copper/zinc superoxide dismutase gene (SOD1). The patient developed bulbar signs followed by rapidly progressive limb muscle weakness. The prominent clinical feature was orthostatic hypotension due to autonomic failure, which occurred after he underwent tracheostomy 1 year and 3 months after the onset. Thereafter, he required mechanical ventilation and progressed to communication stage V (totally locked-in state) 7 years after the onset. Neuropathology showed ALS with posterior column degeneration and multiple system degeneration. Severe neuronal loss in the intermediolateral nucleus was also observed. Two previously reported cases of ALS patients with autonomic failure showed severe neuronal loss in the intermediolateral nucleus in addition to degeneration of the motor neurons. Thus, autonomic failure due to neuronal loss in the intermediolateral nucleus could present in patients with ALS associated with certain mutations in SOD1.

Neuropathology of multiple system atrophy: new thoughts about pathogenesis.

Multiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disorder of uncertain etiology, clinically manifesting with autonomic failure associated with parkinsonism, cerebellar dysfunction, and pyramidal signs in variable combination. The pathological process affects central autonomic, striatonigral, and olivopontocerebellar systems. These show varying degrees of neurodegeneration and underlie the stratification of the heterogenous disorder into MSA-P and MSA-C clinical variants, which correlate to the morphologic phenotypes of striatonigral degeneration and olivopontocerebellar atrophy (MSA-C). The lesions are not limited to these most consistently and severely affected systems but may involve many other parts of the central, peripheral, and autonomic nervous systems, underpinning the multisystem character of MSA. The histological core feature are glial cytoplasmic inclusions (GCIs, Papp-Lantos bodies) in all types of oligodendroglia that contain aggregates of misfolded α-Synuclein (α-Syn). In addition to the ectopic appearance of α-Syn in oligodendrocytes and other cells, oxidative stress, proteasomal and mitochondrial dysfunction, excitotoxiciy, neuroinflammation, metabolic changes, and energy failure are important contributors to the pathogenesis of MSA, as shown by various neurotoxic and transgenic animal models. Although the basic mechanisms of α-Syn-triggered neurodegeneration are not completely understood, neuron-to-oligodendrocyte transfer of α-Syn by prion-like spreading, inducing oligodendroglial and myelin dysfunction associated with chronic neuroinflammation, are suggested finally to lead to a system-specific pattern of neurodegeneration.

Autopsy confirmed multiple system atrophy cases: Mayo experience and role of autonomic function tests.

BACKGROUND: Multiple system atrophy (MSA) is a sporadic progressive neurodegenerative disorder characterised by autonomic failure, manifested as orthostatic hypotension or urogenital dysfunction, with combinations of parkinsonism that is poorly responsive to levodopa, cerebellar ataxia and corticospinal dysfunction. Published autopsy confirmed cases have provided reasonable neurological characterisation but have lacked adequate autonomic function testing. OBJECTIVES: To retrospectively evaluate if the autonomic characterisation of MSA is accurate in autopsy confirmed MSA and if consensus criteria are validated by autopsy confirmation. METHODS: 29 autopsy confirmed cases of MSA evaluated at the Mayo Clinic who had undergone formalised autonomic testing, including adrenergic, sudomotor and cardiovagal functions and Thermoregulatory Sweat Test (TST), from which the Composite Autonomic Severity Score (CASS) was derived, were included in the study. PATIENT CHARACTERISTICS: 17 men, 12 women; age of onset 57±8.1 years; disease duration to death 6.5±3.3 years; first symptom autonomic in 18, parkinsonism in seven and cerebellar in two. Clinical phenotype at first visit was MSA-P (predominant parkinsonism) in 18, MSA-C (predominant cerebellar involvement) in eight, pure autonomic failure in two and Parkinson's disease in one. Clinical diagnosis at last visit was MSA for 28 cases. Autonomic failure was severe: CASS was 7.2±2.3 (maximum 10). TST% was 65.6±33.9% and exceeded 30% in 82% of patients. The most common pattern was global anhidrosis. Norepinephrine was normal supine (203.6±112.7) but orthostatic increment of 33.5±23.2% was reduced. Four clinical features (rapid progression, early postural instability, poor levodopa responsiveness and symmetric involvement) were common. CONCLUSION: The pattern of severe and progressive generalised autonomic failure with severe adrenergic and sudomotor failure combined with the clinical phenotype is highly predictive of MSA.

Cyclin-dependent kinase 5 and mitogen-activated protein kinase in glial cytoplasmic inclusions in multiple system atrophy.

Glial cytoplasmic inclusions (GCI) characteristically occur in the oligodendrocytes of patients with multiple system atrophy (MSA). However, the molecular mechanisms underlying GCI formation are unknown. To investigate whether these inclusions are related to proline-directed protein kinases that have been associated with neuronal inclusion bodies in some other neurodegenerative diseases, we immunohistochemically probed tissue samples from MSA brains with a panel of antibodies against cyclin-dependent kinases and mitogen-activated protein kinase. We unexpectedly detected cyclin-dependent kinase 5- (cdk5) and mitogen-activated protein kinase- (MAPK) immunoreactivities in GCI. We also found TAU1 immunoreactivity in GCI, and a strong expression of microtubule-associated protein (MAP) 2 immunoreactivity in oligodendrocytes of MSA brains. This immunoreactivity was not observed in the normal or neurological controls. The accumulated evidence suggest a close association between GCI and the microtubular cytoskeleton. Cdk5 phosphorylates tau and MAP2, and MAPK is capable of phosphorylating MAP2. The present results suggest that the aberrant or ectopic expression of cdk5 and MAPK causes abnormal phosphorylation of microtubular cytoskeletal proteins, thus leading to GCI formation in affected oligodendrocytes.

What is the accuracy of the clinical diagnosis of multiple system atrophy? A clinicopathologic study.

BACKGROUND: The presentation of symptoms for multiple system atrophy (MSA) varies. Because there are no specific markers for its clinical diagnosis, the diagnosis rests on the results of the neuropathologic examination. Despite several clinicopathologic studies, the diagnostic accuracy for MSA is unknown. OBJECTIVES: To determine the accuracy for the clinical diagnosis of MSA and to identify, as early as possible, those features that would best predict MSA. DESIGN: One hundred five autopsy-confirmed cases of MSA and related disorders (MSA [n=16], non-MSA [n=89]) were presented as clinical vignettes to 6 neurologists (raters) who were unaware of the study design. Raters identified the main clinical features and provided a diagnosis based on descriptions of the patients' first and last clinic visits. METHODS: Interrater reliability was evaluated with the use of kappa statistics. Raters' diagnoses and those of the primary neurologists (who followed up the patients) were compared with the autopsy-confirmed diagnoses to estimate the sensitivity and positive predictive values at the patients' first and last visits. Logistic regression analysis was used to determine the best predictors to diagnose MSA. RESULTS: For the first visit (median, 42 months after the onset of symptoms), the raters' sensitivity (median, 56%; range, 50%-69%) and positive predictive values (median, 76%; range, 61%-91%) for the clinical diagnosis of MSA were not optimal. For the last visit (74 months after the onset of symptoms), the raters' sensitivity (median, 69%; range, 56%-94%) and positive predictive values (median, 80%; range, 77%-92%) improved. Primary neurologists correctly identified 25% and 50% of the patients with MSA at the first and last visits, respectively. False-negative and -positive misdiagnoses frequently occurred in patients with Parkinson disease and progressive supranuclear palsy. Early severe autonomic failure, absence of cognitive impairment, early cerebellar symptoms, and early gait disturbances were identified as the best predictive features to diagnose MSA. CONCLUSIONS: The low sensitivity for the clinical diagnosis of MSA, particularly among neurologists who followed up these patients in the tertiary centers, suggests that this disorder is underdiagnosed. The misdiagnosis of MSA is usually due to its confusion with Parkinson disease or progressive supranuclear palsy, thus compromising the research on all 3 disorders.

Shy-Drager syndrome: neuronal loss depends on size, function, and topography in ventral spinal outflow.

We analyzed myelinated fibers and neurocytons in the ventral spinal outflow of patients with Shy-Drager syndrome. Axonal loss occurred predominantly in thin, myelinated fibers that correspond mainly to autonomic preganglionic axons. Intermediate and large myelinated fibers, mainly gamma and alpha axons, were also involved, but to a lesser degree. Neuronal and axonal loss was more prominent in caudal segments and less in rostral segments. Axonal degeneration in single teased fibers was seen frequently in ventral spinal roots.

Size-dependent myelinated fiber loss in the corticospinal tract in Shy-Drager syndrome and amyotrophic lateral sclerosis.

Morphometric evaluation was performed on myelinated fibers of the corticospinal tract at the seventh thoracic spinal cord segment from three patients with Shy-Drager syndrome (SDS), six patients with amyotrophic lateral sclerosis (ALS), and five patients with nonneurologic symptoms. In SDS, small-sized myelinated fibers were nearly completely depleted, while large-sized myelinated fibers were considerably well preserved. In ALS, on the contrary, large myelinated fibers were predominantly decreased. These results suggested that selective vulnerability of axonal loss depends on fiber size and should be considered in interpretation of pathology of corticospinal tracts.

Cerebellar excitatory and inhibitory amino acid receptors in multiple system atrophy.

We studied excitatory and inhibitory amino acid binding sites autoradiographically in control and multiple system atrophy (MSA) cerebella. Within the dentate nucleus (DN) of MSA specimens, we found a significant increase in the level of GABAA, benzodiazepine, and metabotropic binding sites compared with controls. In the granule cell layer, kainate, N-methyl-D-aspartate, and GABAA binding sites were all decreased significantly in MSA specimens compared with controls. In the molecular layer of MSA cerebellum, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate binding sites were decreased significantly compared with controls. Cerebellar cortical binding site decreases are likely due to Purkinje and granule cell loss. The increase of binding site levels in DN of MSA specimens may represent receptor up-regulation reflecting loss of descending inhibitory Purkinje cell and ascending excitatory afferents to the DN.

Changes in systemic arterial pressure during sleep in Shy-Drager syndrome.

Polygraphic findings during spontaneous nocturnal sleep of 2 patients suffering from Shy-Drager syndrome are reported. In both patients, total sleep time was reduced--sleep latency and awakening periods during the night being increased. Considerable reductions of rapid eye movement (REM) stage and, in 1 patient, also of deep non-REM (NREM; stages 3-4) were found. No apneas were recorded. In normal subjects, systemic systolic and diastolic pressure decreases during all the sleep stages; in our patients, arterial pressure values rose progressively during NREM sleep stages and showed a further increase in REM sleep. In all the sleep stages, sudden phasic swings of systemic arterial pressure were observed.

Survival in multiple system atrophy: a study of prognostic factors in 59 cases.

The various clinical features of multiple system atrophy (MSA) make the diagnosis of the disease difficult, especially in its early stages, when signs of differentiated neuroanatomical system involvement have not yet appeared. Mortality studies may be affected by the variability of the diagnostic criteria and selection bias. We used strict clinical and MRI criteria to diagnose MSA in 59 patients. Patients with parkinsonian and cerebellar onset were compared. Median survival time from the onset of the first motor symptom was 7.5 years. Our results indicated a trend (P = 0.09) for the Northwestern University Disability Scale score to correlate with mortality, but we failed to find other characteristics identifying subgroups or predictors for survival.

A histometrical and comparative study on Purkinje cell loss and olivary nucleus cell loss in multiple system atrophy.

We examined pathologically 21 cases of multiple system atrophy (MSA). Density of Purkinje cell in 16 cases and of olivary nucleus cell in 20 cases was quantitatively measured, and their distribution as well as degree were studied. Contrary to the findings of previous reports, Purkinje cell loss was more pronounced in the vermis than in the hemispheres. Olivary nucleus cell loss was more outstanding in the accessory nucleus than in the inferior nucleus. A topographical characteristic of cell degeneration exists between the Purkinje layer and the olivary nucleus. Significant sparing of the nodulus apparently related to that of the vestibular system was found. While the common distribution of cell loss was seen, its degree varied considerably case by case. The degree was related to both duration of illness and, to some extent, clinical subtypes of MSA.

Distribution of cerebellar cortical lesions in multiple system atrophy: a topographic neuropathological study of three autopsy cases in Japan.

We investigated neuropathologically the distribution of the cerebellar cortical lesions in three Japanese autopsy cases of multiple system atrophy (MSA) using hemisphere specimens. The lesions were classified as mild, moderate or severe. The distribution of cerebellar cortical lesions in all three cases were uniform: the cerebellar cortical lesions were more conspicuous in the vermis than in the hemisphere. These neuropathological findings differ from the established theory that cerebellar lesions of MSA are more pronounced in the hemisphere than in the vermis. The degree of cerebellar cortical lesions in our cases increased in relation to the duration of the disease. Our pathological data may contribute to the morphological differential diagnosis in various neurodegenerative disorders including late cortical cerebellar atrophy. Our neuropathological findings may also make a contribution to the neuroradiological progress in the differential diagnosis of spinocerebellar disease.

Neuronal cell loss of the striatonigral system in multiple system atrophy.

We investigated the longitudinal as well as lateral loss of striatal and nigral cells and its distribution in 7 cases of multiple system atrophy. Loss of striatal small cells and nigral pigmented cells was more prominent in the caudal part than in the rostral and mid-parts. Cell loss was especially high in the dorsolateral zone of the caudal putamen and in the lateral zone of the caudal nigra. These findings indicate that MSA predominantly disturbs the striatal and nigral efferent systems, which interlink the caudal and dorsolateral putamen with the caudolateral nigra. In less severe cases, the rostral to mid-parts of the putamen or substantia nigra were almost intact while its caudal portion was clearly affected. The degenerative process of MSA seems to occur initially in the caudal parts of the putamen and substantia nigra, extending later to the rostral parts. Thus striatal small cells and nigral pigmented cells degenerate according to anatomical relationship. In MSA, degeneration of the striatonigral system could well be explained as being transsynaptic.

Accumulation of tubular structures in oligodendroglial and neuronal cells as the basic alteration in multiple system atrophy.

In 8 brains of patients with various combinations of striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome, inclusion bodies were demonstrated in the cytoplasm and nucleus of both neuronal and oligodendroglial cells and in neuronal processes by means of silver staining, immunocytochemistry and electron microscopy. Differing from oligodendroglial cytoplasmic inclusions recognized by anti-ubiquitin, anti-alpha- and anti-beta-tubulin, and anti-tau antibodies, neuronal cytoplasmic inclusions were stained only by anti-ubiquitin antibody but not with those raised against cytoskeletal proteins. Tubular structures forming the inclusion bodies irrespective of their glial or neuronal location, have fuzzy cover and side extensions which make them similar to the linear structures described in motor neuron diseases. Our study proves that the accumulation of abnormal tubular structures in both oligodendrocytes and neurons is the basic pathological alteration in multiple system atrophy and defines multiple system atrophy as a group of diseases with similar cellular pathology or as a nosological entity.

Shy-Drager syndrome and amyotrophic lateral sclerosis. Cytoarchitectonic and morphometric studies of sacral autonomic neurons.

In order to elucidate the morphological correlates of bladder-rectal dysfunctions in Shy-Drager syndrome, the sacral spinal cord was cytoarchitectonically studied and 3 groups of sacral motor neurons, the posterolateral motor neuron column (PL), inferior intermediolateral nucleus (IML) and cell group X of Onuf (Onuf), were morphometrically quantitated at the S3 level (5 cases), after which the results were compared with those from amyotrophic lateral sclerosis (5 cases) and an age-matched control group (4 cases). The sacral autonomic preganglionic nucleus of IML was localized chiefly in the S3-4 segments and was maximally developed in the caudal one-third of S3. The cell group X of Onuf was localized between the middle of S2 and the rostral one-third of S3 as a longitudinal slender column in the ventral horn. Between these two nuclei at the rostral S3 level, a connecting cellular bridge of neurons of intermediolateral cell type was identified. Morphometry disclosed a marked deprivation of IML, Onuf and somatic motor neurons in Shy-Drager syndrome and a severe loss of somatic motor neurons and a modest deprivation of IML neurons in ALS. These results imply that these two disorders distinguished by different clinical manifestations share a common loss of somatic motor and parasympathetic motor neurons at least in the sacral cord. There are, however, certain gradients in the severity of involvement in these heterogeneous cell groups.

Quantitative study of intermediolateral column cell counts in Machado-Joseph disease.

The number of intermediolateral column (ILC) neurons in 6 alternating segments from the 2nd to 12th thoracic segment of the spinal cord were studied in 4 cases with Machado-Joseph disease (MJD), 3 cases with olivopontocerebellar atrophy (OPCA), a case with Shy-Drager syndrome (SDS), and 5 normal controls. We counted the number of ILC neurons with clearly defined nucleoli in 12 sections of each segment, each section 20 microns thick and taken at 100 microns intervals and then divided the 6 alternating segments into 3 groups, upper (Th2, 4), middle (Th6, 8) and lower (Th10, 12). In each of the three groups of normal control cases, the number of ILC neurons had decreased with aging. In all MJD cases, the number of ILC neurons had moderately decreased in comparison with age-matched controls. One of the MJD cases showed a marked decrease in the number of ILC neurons, as did the SDS case. The ILCs of the entire thoracic spinal cord in the MJD cases were moderately involved.

Ubiquitinated alpha B-crystallin in glial cytoplasmic inclusions from the brain of a patient with multiple system atrophy.

Glial cytoplasmic inclusions (GCIs) have been observed in oligodendroglia-like cells, specifically in the brains of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). We have investigated GCIs from brains of patients with multiple system atrophy biochemically and immunochemically. While most GCIs have been reported positive for both ubiquitin and alpha B-crystallin in immunocytochemical studies, the components of GCIs have not been identified biochemically. GCI-bearing cells were partially purified from the OPCA brain by sieving with nylon meshes and discontinuous sucrose density gradient centrifugation. The fraction containing GCI-bearing cells was also found to contain a 32 kDa and a 40 kDa protein, both of which were specifically recognized by anti-ubiquitin and anti-alpha B-crystallin antibodies, neither of which was found in the same fraction derived from control brain. These immunochemical results suggest that ubiquitinated alpha B-crystallin is present in GCIs from the brains of patients with multiple system atrophy.

Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome).

Glial cytoplasmic inclusions (GCIs) were demonstrated by silver staining, immunocytochemistry and by electron microscopy in the central nervous system (CNS) of 11 patients with various combinations of striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome. Although their configuration in light microscope can sometimes resemble neurofibrillary tangles, their cellular localisation, measurements, ultrastructure, immunocytochemical characteristics and regional distribution all differ from these Alzheimer type changes. The majority of GCIs were localized in the white matter and appeared to be accompanied by an increase in the number of interfascicular oligodendroglial cells and pallor or loss of myelin staining. Our histological, ultrastructural and immunocytochemical findings all indicate that the cells which contain GCIs are oligodendrocytes and the inclusions themselves are composed of tubular structures. The presence of the until now unknown GCIs in all the 11 CNS, but not in age- and sex-matched control brains, indicates that GCI is a cellular change characteristic of multiple system atrophy and the three syndromes are various manifestations of the same disease.

Immunohistochemical expression of microtubule-associated protein 5 (MAP5) in glial cells in multiple system atrophy.

An immunohistochemical study focusing on glial cells was performed using monoclonal antibodies against microtubule-associated proteins (MAP1, MAP2 and MAP5), transferrin, leukocyte common antigen (LCA) and glial fibrillary acidic protein (GFAP) in 5 cases of multiple system atrophy (MSA) exhibiting olivopontocerebellar atrophy and striatonigral degeneration. An antibody to MAP5, a fetal antigen in developing brain, was strongly demonstrated in the glial cytoplasmic inclusions (GCIs) which have recently drawn a great deal of attention and were observed in all 5 cases of MSA. Moreover, MAP5-positive glial cells (MAP5-Gs) were present in significantly higher number than in the controls in various regions where GCIs were found, predominantly in putamen, substantia nigra, cerebellar white matter and internal capsule. LCA and transferrin, markers of microglia and oligodendroglia, respectively, were immunohistochemically detected in some MAP5-Gs. GFAP, on the other hand, was not expressed in MAP5-Gs at all. These findings suggest that MAP5-Gs consist of reactive microglia and oligodendroglia. Our study is the first to demonstrate immunohistochemical detection of MAP5 in glial pathological changes in MSA.