Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We undertook this study to investigate the neuropathologic relationships among Alzheimer disease (AD), idiopathic Parkinson disease (PD), and the Lewy body variant of AD (AD/LBV). We retrieved 30 autopsy cases in which Lewy bodies (LB) had been identified in the substantia nigra (SN) in routine hematoxylin-eosin-stained sections. Twenty-two of the cases had a primary clinical diagnosis of dementia and neuropathologic changes of AD; 12 of these demented patients also had clinical parkinsonism. Eight cases had clinical and neuropathologic evidence of PD with minimal or no AD neuropathology, though 6 had clinical dementia. Controls consisted of 6 cases of AD without SN LB by hematoxylin-eosin, and 5 neurologically normal aged controls. Paraffin sections of SN, superior temporal gyrus, and cingulate gyrus from each case were immunostained with rabbit anti-ubiquitin antiserum, randomized, and analyzed individually by light microscopy, and the density of LB-like profiles in each section were graded. None of 5 nondemented aged controls showed any neocortical LB, even though 2 had significant numbers of incidental SN LB by ubiquitin immunostaining. Of 6 AD cases without SN LB by hematoxylin-eosin, 3 had rare SN LB on ubiquitin stain, 1 of which showed rare neocortical Lewy-like profiles. Seven of 8 PD cases showed neocortical LB, including the 6 with dementia. Twenty-one of 22 AD cases with SN LB showed ubiquitin-immunoreactive Lewy-like bodies in the neocortex that were statistically significantly greater in number than in either pure PD or pure AD cases. The frequent occurrence of LB in the neocortex in PD alone suggests that AD/LBV likely represents mixed AD/PD. However, AD neuropathology may favor or promote the formation of neocortical LB in patients who go on to develop mixed AD/PD pathology.
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PMID:Neuropathologic evidence that the Lewy body variant of Alzheimer disease represents coexistence of Alzheimer disease and idiopathic Parkinson disease. 959 17

Lewy bodies and Lewy neurites are the defining neuropathological characteristics of Parkinson's disease and dementia with Lewy bodies. They are made of abnormal filamentous assemblies of unknown composition. We show here that Lewy bodies and Lewy neurites from Parkinson's disease and dementia with Lewy bodies are stained strongly by antibodies directed against amino-terminal and carboxyl-terminal sequences of alpha-synuclein, showing the presence of full-length or close to full-length alpha-synuclein. The number of alpha-synuclein-stained structures exceeded that immunoreactive for ubiquitin, which is currently the most sensitive marker of Lewy bodies and Lewy neurites. Staining for alpha-synuclein thus will replace staining for ubiquitin as the preferred method for detecting Lewy bodies and Lewy neurites. We have isolated Lewy body filaments by a method used for the extraction of paired helical filaments from Alzheimer's disease brain. By immunoelectron microscopy, extracted filaments were labeled strongly by anti-alpha-synuclein antibodies. The morphologies of the 5- to 10-nm filaments and their staining characteristics suggest that extended alpha-synuclein molecules run parallel to the filament axis and that the filaments are polar structures. These findings indicate that alpha-synuclein forms the major filamentous component of Lewy bodies and Lewy neurites.
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PMID:alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies. 960 Sep 90

We investigated the role of cortical Lewy bodies (LB) and Alzheimer-type changes in cognitive impairment in patients with idiopathic Parkinson's disease (PD). We evaluated 44 cases for the extent of neuropathological lesions with a CERAD neuropathological assessment battery and the stage of dementia using Reisberg's global deterioration scale (GDS). Substantia nigra, amygdala, hippocampus and cerebral cortex were examined for LB and Alzheimer-type changes. For detection of LB, the cortical areas were stained with polyclonal antibodies against ubiquitin and tau. We found at least one cortical LB in 93% of cases. Furthermore, 43% of the cases had histological findings of definite Alzheimer's disease (AD). The association between cognitive impairment and the number of cortical LB and Alzheimer-type changes in the amygdala, hippocampus and six selected gyri from cerebral cortex were analyzed using stepwise linear regression. In this analysis the total number of cortical LB, and the amount of neurofibrillary tangles in the temporal cortex remained statistically significant. When the cases with neuropathological changes consistent with a diagnosis of AD were excluded, the correlation between the total number of cortical LB and cognitive impairment was more obvious. A stepwise linear regression analysis in these cases found the total number of cortical LB to be the statistically significant predictor of cognitive impairment. This study revealed that LB densities in the cortex, especially in the temporal neocortex, correlated significantly with the cognitive impairment in PD independent of or in addition to Alzheimer-type pathology.
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PMID:Cortical Lewy bodies and Alzheimer-type changes in patients with Parkinson's disease. 965 Jul 49

Little is currently known concerning the cellular substrates for, and the mechanisms mediating the pathological deposition of, redox-active brain iron in Parkinson's disease. In various subcortical brain regions, populations of astroglia progressively accumulate peroxidase-positive cytoplasmic inclusions derived from effete, iron-laden mitochondria. In the present study, histochemical, ultrastructural, and elemental microanalytical techniques were used to demonstrate the existence of peroxidase-positive astroglia in the substantia nigra of adult rats. At 4 months of age and earlier, few GFAP-positive nigral astroglia contained small, electron-dense cytoplasmic inclusions which exhibited faint endogenous peroxidase activity (diaminobenzidine reaction product) and no detectable iron by microprobe analysis. In contrast, by 14-18 months of age, there was a significant, fourfold increase in numbers of peroxidase-positive astrocyte inclusions in the substantia nigra. The nigral gliosomes in the older animals were heterogeneously electron dense, immunoreactive for ubiquitin and a mitochondrial epitope, and often exhibited X-ray emission peaks for iron. Copper peaks were also detected in a minority of nigral gliosomes. Previous in vitro work indicated that the iron-mediated peroxidase activity in these cells promotes the bioactivation of dopamine and other catechols to neurotoxic free radical intermediates. Thus, mitochondrial sequestration of redox-active iron in aging nigral astroglia may be one factor predisposing the senescent nervous system to parkinsonism and other neurodegenerative disorders.
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PMID:Astrocyte mitochondria: a substrate for iron deposition in the aging rat substantia nigra. 971 May 17

A coding substitution (I93M) in the ubiquitin carboxy-terminal L1 (UCH-L1) gene has recently been identified in a German family with Parkinson's disease. We have sequenced the entire coding region of the gene in 11 families who have a pattern of disease consistent with autosomal dominant inheritance. We found a polymorphism (S18Y) in exon 3, two polymorphisms in the 5' non-coding region, upstream of the transcription start, and an insertion/deletion polymorphism in intron 4. The S18Y allele is present on approximately 20% of chromosomes in a Caucasian population. These changes are, therefore, unlikely to be pathogenic. We conclude that the I93M variant must either be a rare cause of disease or a harmless substitution whose occurrence in the family reflects a chance co-occurrence.
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PMID:Low frequency of pathogenic mutations in the ubiquitin carboxy-terminal hydrolase gene in familial Parkinson's disease. 1020 48

Lewy bodies (LB) and pale bodies (PB), their putative precursors, can be found in a spectrum of diseases characterized by parkinsonism and/or dementia. Furthermore, LB are occasionally observed in some other neurodegenerative diseases and in normal aging. Classical LB are typically found in the brain stem, especially in the substantia nigra, where these inclusions are associated with neuronal loss and clinical signs of idiopathic Parkinson's disease (PD). The so-called cortical LB occur in the cerebral cortex, amygdala and claustrum with little or no neuronal loss and are clinically associated with dementia in dementia with LB (DLB). We describe a patient without apparent clinical signs of parkinsonism and/or dementia, whose brain contained numerous classical-like LB, pale inclusions with features of PB and transitions between these two. These inclusions had similar immunohistological (ubiquitin positive; neurofilament positive; tau negative) and ultrastructural features as the LB in PD and DLB except for the lack of immunoreactivity for alpha-synuclein. The pons and cerebral cortex showed the highest number of LB, up to 165/1.76 mm2. These numbers were contrasted by the lack of obvious neuronal loss or gliosis. The absence of alpha-synuclein reactivity in the LB in this symptomless patient corroborates the hypothesis that alpha-synuclein accumulation in LB is an important step in neurodegeneration in PD and DLB, but tones down the role of alpha-synuclein in LB formation in general. This patient seems to represent a new variant in the spectrum of diseases associated with LB.
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PMID:Numerous and widespread alpha-synuclein-negative Lewy bodies in an asymptomatic patient. 1033 93

It has been suggested that dystrophic neurites in the hippocampal CA2-3 sector are characteristic of diffuse Lewy body disease (DLBD) but not of Parkinson's disease (PD). We investigated the severity of neuritic change in the CA2-3 sector of the hippocampus and in the periamygdaloid cortex (PAC) in 45 patients with clinically diagnosed and neuropathologically verified PD. Samples from amygdala, hippocampus, entorhinal cortex (ERC) and cortical gyri were examined for Alzheimer-type (AD) changes and Lewy bodies (LBs) using antibodies against ubiquitin and tau. Ubiquitin-positive but polyclonal tau-negative neurites were detected in the CA2-3 region of the hippocampus in 88% of patients and in the PAC in 91% of patients. The CA2-3 sector neurites correlated significantly only with LBs in all other brain areas, except in the amygdala. The neurites in the PAC correlated significantly with neuropathological variables in all other brain areas examined, except with tangles in the pre-central and frontal gyrus and with LBs in the amygdala and in the ERC. Unlike in the CA2-3 sector, the neuritic change in the PAC was more prominent in those PD patients with more severe cognitive impairment (P = 0.03). There was no significant correlation between the apoE4 allele load and the neuritic change in the PAC or in the CA2-3 sector. Our study revealed that cortical LBs and neuritic change in the amygdala and hippocampal CA2-3 sector co-exist in PD. Unlike hippocampal neurites, the PAC neurites are related to AD pathology. There seems to be a relationship between the PAC neurites and cognitive impairment in PD, but its significance needs further elucidation.
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PMID:Neuritic degeneration in the hippocampus and amygdala in Parkinson's disease in relation to Alzheimer pathology. 1044 55

Lewy body (LB) is consistently found in the substantia nigra in Parkinson's disease. We report a 68-year-old woman with late-onset, dopa-responsive parkinsonism. Her parents were first cousins, but no other affected individuals were present in the family. Autopsy revealed moderate loss of pigmented neurons with gliosis, but neither LBs nor neurofibrillary tangles in the substantia nigra. The locus ceruleus showed neuronal loss with scarce LBs. The most striking change was found in the dorsal vagal nucleus, where marked neuronal loss and fibrillary gliosis with many LBs were evident. Despite the use of ubiquitin and alpha-synuclein immunohistochemistry, no further LBs were identified in other brain regions. These findings suggest that this case was an unusual, anatomically restricted manifestation of LB disease.
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PMID:Restricted occurrence of Lewy bodies in the dorsal vagal nucleus in a patient with late-onset parkinsonism. 1045 Aug 7

Recently an Ile93Met mutation in the ubiquitin-carboxy-terminal-hydrolase-L1 gene (UCH-L1) has been described in a German family with Parkinson's disease (PD). The authors showed that this mutation is responsible for an impaired proteolytic activity of the UCH-L1 protein and may lead to an abnormal aggregation of proteins in the brain. In order to determine the importance of this or any other mutation in the coding region of the UCH-L1 gene in PD, we performed mutation analysis on Caucasian families with at least two affected sibs. We did not detect any mutations in the UCH-L1 gene, however, we cannot exclude mutations in the regulatory or intronic regions of the UCH-L1 gene since these regions were not sequenced. We conclude that the UCH-L1 gene is not a major gene responsible for familial PD.
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PMID:The Ile93Met mutation in the ubiquitin carboxy-terminal-hydrolase-L1 gene is not observed in European cases with familial Parkinson's disease. 1045 31

The cause of the selective degeneration of nigrostriatal neurons in Parkinson disease (PD) has remained largely unknown. Exceptions include rare missense mutations in the alpha-synuclein gene on chromosome 4, a potentially pathogenic mutation affecting the ubiquitin pathway, and mutations in the parkin gene on chromosome 6. However, unlike classical PD, the latter syndrome is not associated with the formation of typical Lewy bodies. In contrast, a biochemical defect of complex I of the mitochondrial respiratory chain has been described in a relatively large group of confirmed PD cases. Recent cybrid studies indicate that the complex I defect in PD has a genetic cause and that it may arise from mutations in the mitochondrial DNA. Sequence analysis of the mitochondrial genome supports the view that mitochondrial point mutations are involved in PD pathogenesis. However, although mitochondria function as regulators in several known forms of cell death, their exact involvement in PD has remained unresolved. This is of relevance because classical apoptosis does not appear to play a major role in the degeneration of the parkinsonian nigra.
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PMID:Role of mitochondria in Parkinson disease. 1049 35


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