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Juvenile parkinsonism (onset age <20 yrs) is uncommon and few cases with neuropathologic confirmation have been reported. We present the case of a 17-year-old boy who presented with asymmetric arm tremor and bulbar symptoms. His paternal great aunt had parkinsonism with onset at age 22 years. Examination revealed parkinsonism in the absence of additional neurologic signs except for delayed pupillary responses to light. He responded well to levodopa but developed motor fluctuations and disabling dyskinesias after 3 years of treatment. Following attempted withdrawal of levodopa at age 24 years, he developed severe aspiration pneumonia complicated by cardiorepiratory arrests and he died 6 months later. At autopsy, the dominant histologic feature was wide-spread neuronal hyaline intranuclear inclusions. Neuronal depletion was observed in the substantia nigra, locus ceruleus, and, to a lesser extent, in the frontal cortex, and inclusions were particularly prominent in these areas. Inclusions were immunoreactive for ubiquitin and were typical of those seen in neuronal intranuclear inclusion disease (NIID), a rare, multisytem neurodegenerative disease. NIID should be considered in the differential diagnosis of juvenile parkinsonism. A link between NIID and hereditary neurodegenerative disorders characterized by expanded polyglutamine tracts is supported by the similar appearance of intranuclear inclusions in both conditions and by a family history in some cases of NIID.

The cause and mechanism of neuronal cell death in the substantia nigra of patients with Parkinson's disease (PD) are unknown. There is also controversy about whether the cell death results from a single event followed by cell loss consistent with aging or whether there is an ongoing pathologic process. Using postmortem tissue obtained from the Parkinson's Disease Society Brain Tissue Bank in London, we have sought to establish whether apoptosis, or more specifically DNA fragmentation of neurons, is a prominent feature of nigral pathology. In addition, we have studied microglial activation in the substantia nigra as an indicator of ongoing pathology using the highly sensitive markers CR3/43 and EBM11. Reactive astrocytes have been assessed using immunostaining for glial fibrillary acidic protein (GFAP). Ten patients with pathologically proven PD were studied. In all cases, regardless of disease duration, severity, drug treatment, or age of the patient, there was no evidence of apoptosis in the substantia nigra as assessed by in situ end-labeling of DNA fragments using biotinylated dUTP and terminal deoxynucleotidyl transferase (TdT). In contrast, a case of multiple system atrophy (MSA) served as a positive control for the technique. In this case, positive DNA end-labeling could be found in neurons and non-neuronal cells in the brain stem. In the PD cases, there was, however, localized pathology in the substantia nigra as revealed by the CR3/ 43 and EBM11 markers for activated microglia. This process seemed independent of disease duration and was florid even in patients with severe neuronal loss. It remains to be determined to what extent the activation of glial cells reflects progressive nigral pathology, and whether those factors which are classically associated with prominent apoptotic neuronal cell death in vivo, such as neurotrophic factor deprivation, are prime causes of nigral neuronal loss in PD. Future studies should focus on recent-onset PD or incidental Lewy body disease to further address these questions.

Multiple system atrophy (MSA) is a clinico-pathological entity distinct from idiopathic Parkinson's disease (PD) that is responsible for 5-10% of cases of parkinsonism. Degeneration of nigral neurones is a feature of both diseases. A specific deficiency of mitochondrial complex I activity has been found in PD substantia nigra. We have analysed mitochondrial function in substantia nigra and platelets from MSA patients to identify any respiratory chain defect in this disorder and to determine its tissue specificity. As our MSA patients had been on L-DOPA, we also sought to establish whether this treatment could cause the complex I defect as seen in PD. We found no significant difference in respiratory chain activity corrected for mitochondrial mass between control and MSA patients in either of the tissues studied. These results provide a biochemical dimension to the differences between MSA and idiopathic PD. In addition, the fact that L-DOPA failed to induce a complex I defect in MSA substantia nigra suggests that this treatment is unlikely to cause the complex I deficiency in PD, without additional factors that may operate in PD.

We report the clinicopathological features of 203 cases of pathologically proven multiple system atrophy (MSA) from 108 publications up to February 1995. The majority of patients showed symptoms in their early fifties, and men were more commonly affected than women (ratio of 1.3:1). Most patients suffered from some degree of autonomic failure (74%). Parkinsonism was the most common motor disorder (87%), followed by cerebellar ataxia (54%) and pyramidal signs (49%). The response to levodopa was poor in most patients, but there was a subgroup with a good response, who also often developed axial levodopa-induced dyskinesias. Other characteristic features included severe dysarthria, stridor, and, in a few patients, contractures and dystonia (antecollis). Mild or moderate intellectual impairment occurred in some cases, but severe dementing illness was most unusual. The main pathological change comprised cell loss and gliosis in the putamen, caudate nucleus, external pallidum, substantia nigra, locus ceruleus, inferior olives, pontine nuclei, cerebellar Purkinje cells, and intermediolateral cell columns of the spinal cord. However, other neuronal populations were also involved to varying degrees, such as the thalamus, vestibular nucleus, dorsal vagal nucleus, corticospinal tracts, and anterior horn cells. Characteristic glial and/or neuronal cytoplasmic inclusions were identified in all cases in which they were sought, irrespective of clinical presentation. Akinesia correlated with the degree of nigral and putaminal cell loss, whereas rigidity was related only to the later. Tremor was unrelated to cell loss at any site. Ataxia correlated with the degree of olivopontocerebellar atrophy. Pyramidal signs were associated with pyramidal tract pallor. Our analysis also confirmed an association of postural hypotension with intermediolateral cell column degeneration.

It is not known whether an increased incidence of dementia in patients with Parkinson's disease (PD) is due to a higher incidence of Alzheimer's disease (AD) or to "early" Alzheimer-type pathology. To determine whether amyloid beta-peptide (A beta) of AD occurs more frequently in brains of patients with PD, we examined 50 cases and 79 controls by using histoblots for A beta. Twenty-three cases with PD had dementia, including all nine with A beta distributed throughout the entire cerebral cortex; three of these cases had AD. In contrast, five of 17 controls with comparable A beta accumulation were not demented. Neither AD nor A beta deposition was increased in PD, furthermore, there was no statistical correlation between the amount of A beta and the number of Lewy bodies in cerebral cortex. In 14 patients with PD in whom dementia was unrelated to A beta, there was cerebral vascular disease (four), numerous cortical Lewy bodies (three), or hydrocephalus (two); in five further cases, dementia was not well explained by histopathologic changes. Our data found no increase of either AD or "early" Alzheimer-type pathology in cases of PD; however, a synergistic effect between the two pathologies was suggested as contributing to dementia.

Olivopontocerebellar atrophy (OPCA) is widely accepted as part of the neuropathological spectrum of multiple system atrophy (MSA). The distribution of affected sites in the olivopontocerebellar (OPC) system and their interrelationship remain poorly understood due to lack of quantitative studies. To further investigate the OPC pathology in MSA, we performed a morphometric analysis of 20 MSA cases and eight healthy controls. In the MSA cases, mean neuronal cell densities were significantly reduced in (medial and dorsal) accessory and principal inferior olives, pontine nuclei, cerebellar vermis (except nodulus), and hemispheres. Inferior olives and pontine nuclei were more severely affected than cerebellar Purkinje cells in most cases. Cerebellar Purkinje cells were more severely depleted in vermis rather than in hemisphere. There was a poor topographic correlation between neuronal cell loss in inferior olives and cerebellar cortex. These results suggest a primary degeneration of olivopontine nuclei and cerebellar Purkinje cells in OPCA. Inferior olives, pontine nuclei and cerebellar cortex were all significantly more severely affected in cases with a pure or predominating cerebellar syndrome (OPCA type, n = 4) compared to those with pure or predominating parkinsonism (SND type, n = 14). However, although cerebellar signs had been noted in life in only six cases, morphometry revealed OPCA in 17 of the 20 MSA brains.

There is evidence for a 37% deficiency of complex I activity in Parkinson's disease (PD), which appears to be specific for PD amongst parkinsonian syndromes and selective for the substantia nigra within the central nervous system. Rat studies have shown that, in the context of a normal nigrostriatal dopaminergic cell population, L-dihydroxyphenylalanine (L-dopa) causes a reversible 25% defect of complex I activity in nigral and striatal tissue. Analysis of striatal tissue from PD patients after prolonged exposure to high-dose L-dopa does not show such a defect. Results of these and other studies suggest that L-dopa therapy does not cause complex I deficiency in PD striatum. However, it cannot be excluded that, in the particular environment of the PD substantia nigra, L-dopa may enhance a preexisting complex I defect.

Molecular genetic studies of the cytochrome P450 system enzyme CYP2D6, which hydroxylates debrisoquine, have indicated an excess of mutant alleles in large series of patients with Parkinson's disease (PD) when compared with controls. We have investigated CYP2D6 polymorphism in 91 patients with multiple system atrophy (MSA) in order to determine if this finding is specific to PD or if there is similar evidence of genetic susceptibility to neurotoxicity in MSA. The distribution of CYP2D6 alleles was not significantly different between MSA patients and controls, and there were fewer poor metabolisers in the MSA group than in the control group.

Impaired olfaction occurs in patients with idiopathic Parkinson's disease (PD), and Lewy bodies have been found in the olfactory bulb and tract. We now confirm the latter finding and show that this presence of Lewy bodies is associated with significant neuronal loss. A quantitative study of the anterior olfactory nucleus (AON) was performed in tissue obtained postmortem from seven patients with PD and seven age-matched controls. Neuronal loss was seen in the PD bulb and tracts (p < 0.01), and a strong correlation of neuronal loss with disease duration was detected (R = -0.87). The presence of Lewy bodies was confirmed with immunocytochemical staining for ubiquitin in all the PD cases.

An 81-year-old woman died after a 3-year history of a progressive nondementing akinetic-rigid syndrome. Initially, there was a moderate response to levodopa treatment. Subsequently she developed postural tremor, loss of upward gaze, and frequent falls suggestive of Steele-Richardson-Olszewski syndrome (SROS). Macroscopical examination showed depigmentation of substantia nigra and locus ceruleus. Histology revealed occasional swollen achromatic neurons predominantly in frontal cortex, small cortical neurofibrillary tangles, brain stem basophil (corticobasal) inclusions, and Pick bodies. The coexistence of these histopathological markers raises questions concerning their specificity and the basis of a morphological distinction between corticobasal degeneration and Pick's disease.

Elevated iron levels, enhanced oxidative damage, and complex I deficiency have been identified in the substantia nigra of Parkinson's disease patients. To understand the interrelationship of these abnormalities, we analyzed iron levels, ferritin levels, and complex I activity in the substantia nigra of patients with Parkinson's disease. Total iron levels were increased significantly, ferritin levels were unchanged, and complex I activities were decreased significantly in the substantia nigra samples. The failure of ferritin levels to increase with elevated iron concentrations suggests that the amount of reactive iron may increase in the substantia nigra of Parkinson's disease patients. There was no correlation between the iron levels and complex I activity or the iron-ferritin ratio and complex I activity in the substantia nigra samples.

In this article we describe the neuropathological changes in three patients with neuroacanthocytosis and review the neuropathology of the other eight cases reported in the literature. Macroscopically the brains showed enlargement of the lateral ventricles, especially the frontal horns. The most severely and consistently affected brain areas were the caudate nucleus and putamen, which were atrophic and showed by light microscopy marked neuronal loss and gliosis. Small and medium-sized striatal neurons were particularly depleted. The globus pallidus was almost as severely involved as the striatum. In some cases the thalamus, substantia nigra, and anterior horns of the spinal cord showed pathology, mainly neuronal loss and mild gliosis. Brain areas with no pathology included the subthalamic nucleus, cerebral cortex, cerebellum, pons, and medulla. The preservation of these areas may help in the neuropathological distinction of neuroacanthocytosis from Huntington's disease.

Cranial computer tomographic (CT) images of 33 patients with multiple system atrophy (MSA) and of 40 age-matched controls were blindly analyzed by two neuroradiologists. All patients had autonomic dysfunction, all but one had parkinsonism, and 13 had cerebellar signs. The scans were judged entirely normal in 21%. Moderate or severe infratentorial atrophy was found in 42%. Cerebellar atrophy was present in 39%, and pontine atrophy was present in 18%. Of the 13 patients with cerebellar signs, only eight had cerebellar atrophy. Of the 20 patients without cerebellar signs, five had cerebellar atrophy. Supratentorial involvement was much less common and less severe. Thus, CT demonstrated system involvement that was not evident clinically in five of 33 cases (15%). However, in all five the clinical diagnosis was already evident from the presence of both autonomic and pyramidal signs in addition to parkinsonism. We conclude that CT imaging is of limited diagnostic use in individual patients with MSA.

We describe the pathological findings in two patients who developed atypical parkinsonism and autonomic failure, leading to a diagnosis of multiple system atrophy (MSA). Postmortem examination of the brain showed cell loss restricted to substantia nigra and locus coeruleus. However, glial cytoplasmic inclusions (GCIs) were present in both cases. We propose that GCIs are highly suggestive of a pathological diagnosis of MSA in the absence of detectable cell loss outside pigmented brain stem nuclei and that brains from cases of atypical parkinsonism should routinely be examined for their presence.

Previous studies examining the involvement of oxidative stress in the substantia nigra in Parkinson's disease have measured terminal products of lipid peroxidation or the function of antioxidant defense systems. We report a more specific early marker of lipid peroxidation, lipid hydroperoxides, in a high-performance liquid chromatography (HPLC) and electron spin resonance (ESR) investigation. HPLC-chemiluminescent detection revealed two classes of lipid hydroperoxides in brain tissue extracts--free fatty acid hydroperoxides and cholesterol lipid hydroperoxides. Only cholesterol lipid hydroperoxides were consistently detected in all tissue extracts. Cholesterol lipid hydroperoxides had a 10-fold increase in the Parkinson's disease substantia nigra compared to control subjects. ESR detection of radical degradation products, including those of lipid hydroperoxides, in nigral homogenates incubated with the spin trap N-t-butyl-alpha-phenyl nitrone (PBN) showed a marked variation in ESR signal between tissues. Despite the increased levels of lipid hydroperoxides in parkinsonian substantia nigra, there was no overall difference in ESR signal intensity between nigral tissues from controls and from patients with Parkinson's disease. The increased levels of an early component of the peroxidation chain in substantia nigra in Parkinson's disease support the hypothesis of a continuous toxic process involving oxygen radical activity. However, using previously frozen tissue, ESR evidence for increased radical formation could not be demonstrated.

Brain tissue from normal individuals with incidental Lewy bodies and cell loss in pigmented substantia nigra neurons (asymptomatic Parkinson's disease) and age-matched control subjects without nigral Lewy bodies was examined biochemically. There was no difference in dopamine levels or dopamine turnover in the caudate and putamen of individuals with incidental Lewy body disease compared to control subjects. There were no differences in levels of iron, copper, manganese, or zinc in the substantia nigra or other brain regions from the individuals with incidental Lewy body disease compared to those from control subjects. Similarly, ferritin levels in the substantia nigra and other brain areas were unaltered. There was no difference in the activity of succinate cytochrome c reductase (complexes II and III) or cytochrome oxidase (complex IV) between incidental Lewy body subjects and control subjects. Rotenone-sensitive NADH coenzyme Q1 reductase activity (complex I) was reduced to levels intermediate between those in control subjects and those in patients with overt Parkinson's disease, but this change did not reach statistical significance. The levels of reduced glutathione in substantia nigra were reduced by 35% in patients with incidental Lewy body disease compared to control subjects. Reduced glutathione levels in other brain regions were unaffected and there were no changes in oxidized glutathione levels in any brain region. Altered iron metabolism is not detectable in the early stages of nigral dopamine cell degeneration. There may be some impairment of mitochondrial complex I activity in the substantia nigra in Parkinson's disease.(ABSTRACT TRUNCATED AT 250 WORDS)

A family with autosomal dominant inheritance of an early-onset and rapidly progressive parkinsonian syndrome and associated severe depression is reported. Three members had parkinsonism with depression, 3 had parkinsonism alone, and 2 suffered depression only. Pathological brain examination in 2 members with parkinsonism and depression revealed distinctive changes, with devastation of the substantia nigra, scarce Lewy bodies, and gliosis of the caudate nucleus and globus pallidus. The clinical and pathological findings were similar to those in four previously described families with autosomal dominant parkinsonism, depression, and alveolar hypoventilation.

We report a patient with cranial dystonia who also had rest tremor of one arm and who developed drug-induced parkinsonism on treatment. The patient's brain was normal on autopsy. We also review the findings in the few reported cases of cranial dystonia with pathology.

A 67-year-old man with a family history of parkinsonism had visual complaints due to difficulty in convergence, which was followed 2 years later by development of bradykinesia and rigidity. The diagnosis of Steele-Richardson-Olszewski syndrome was made on the basis of a supranuclear gaze palsy, bradykinesia, rigidity, and poor response to levodopa. However, subsequent neuropathological examination revealed diffuse Lewy body disease with no evidence of neurofibrillary tangles involving either subcortical or brain stem structures.

alpha-Tocopherol (vitamin E) levels in normal brain were lower in the cerebellum than in the cerebral cortex or basal ganglia. There was no difference in alpha-tocopherol levels in the cerebellum, basal ganglia, or cerebral cortex between control subjects and patients with Parkinson's disease.

The clinical and postmortem findings of a patient with Lewy body pathology combined with multiple-system atrophy are described. When alive the patient was diagnosed as having Parkinson's disease. Pathological examination found evidence of striatonigral and olivopontocerebellar degeneration, together with Lewy bodies at a number of sites characteristic for idiopathic Parkinson's disease. Taken together, the clinical history and histological findings support the coexistence of two disease processes.