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S Kösel

Publications and source records attributed to S Kösel.

34 records · Page 2Linked to original sources
PubMed1997

On the question of apoptosis in the parkinsonian substantia nigra.

Apoptosis has been postulated as a mechanism of nerve cell death in Parkinson's disease. In the present study, the substantia nigra of 22 neuropathologically confirmed Parkinson cases and 8 control brains was studied using the in situ end-labeling (TUNEL) method. About 50% of parkinsonian brains showed a small number of TUNEL-positive glial cells in the substantia nigra, whereas no neurons showed convincing TUNEL positivity or any morphological signs of apoptosis. No correlation was observed between the number of TUNEL-positive glial cells and microglial activation. Our results fail to demonstrate apoptosis as a mechanism of cell death in Parkinson's disease.

Aged↗
PubMed1997

Low prevalence of apolipoprotein E epsilon 4 allele in the neurofibrillary tangle predominant form of senile dementia.

Apolipoprotein E (apoE) genotypes were analyzed in a subset of demented very old patients who share a uniform neuropathological picture consisting of various numbers of neurofibrillary tangles (NFT) in allocortical areas of the inferomedial temporal lobe without significant numbers of either diffuse amyloid or neuritic plaques. Among 18 patients with this condition referred to as NFT-predominant senile dementia (average age at death 87 +/- 4.7 years), we found allele frequencies of 0.11 epsilon 2, 0.86 epsilon 3 and 0.03 epsilon 4, which are significantly different from allele frequencies reported in Alzheimer's disease (0.04 epsilon 2, 0.59 epsilon 3 and 0.38 epsilon 4). The low prevalence of the apoE epsilon 4 allele in this subset of patients is striking and suggests that NFT-predominant senile dementia is a dementing neurodegenerative disease in which the deposition of A beta-amyloid did not occur, possibly due to protective effects of epsilon 2 and/or epsilon 3 alleles or lack of a promoting effect of apoE epsilon 4 on amyloidogenesis. We propose that NFT-predominant dementia is a variant of Alzheimer's disease occurring in the very old.

Aged↗
PubMed1997

Long-lasting perivascular accumulation of major histocompatibility complex class II-positive lipophages in the spinal cord of stroke patients: possible relevance for the immune privilege of the brain.

Six cases of middle cerebral artery occlusion are presented in which the cellular changes accompanying descending degeneration of the lateral corticospinal tract were studied at different time points (5 days-10 years) following the insult. Microglia and perivascular cells were found to ingest large amounts of myelin degradation products, while expressing high levels of major histocompatibility complex (MHC) class II molecules. Activation of perivascular macrophages, as indicated by increased class II expression, lasted for many years and appeared to follow down-regulation of both phagocytic activity and class II expression on parenchymal microglia. TUNEL labeling was absent from both microglia and perivascular cells at all time points investigated. Indirect evidence is presented that microglia may transfer myelin degradation products to the perivascular space. Perivascular cells which express MHC class II molecules constitutively do not appear to leave the perivascular compartment in large numbers and could release myelin degradation products into the cerebrospinal fluid. The possible immunological consequences of these findings are discussed with respect to their possible relevance for antigen presentation and autoimmune central nervous system disease.

Adult↗
PubMed1997

Rediscovery of the case described by Alois Alzheimer in 1911: historical, histological and molecular genetic analysis.

In 1911, Alois Alzheimer published a detailed report (Zbl. ges. Neurol. Psych. 4: 356-385) on a peculiar case of the disease that had been named after him by Emil Kraepelin in 1910. Alzheimer describes a 56-year-old male patient (Johann F.) who suffered from presenile dementia and who was hospitalized in Kraepelin's clinic for more than 3 years. Post-mortem examination of the patient's brain revealed numerous amyloid plaques but no neurofibrillary tangles in the cerebral cortex, corresponding to a less common form of Alzheimer disease which may be referred to as 'plaque only'. We have identified well-preserved histological sections of this case and performed mutational screening of exon 17 of the amyloid precursor protein gene and genotyping for apolipoprotein E alleles. The patient was shown to be homozygous for apolipoprotein allele epsilon3 and lacked APP mutations at codons 692, 693, 713 and 717. This case is of historical importance as it may have convinced Kraepelin to name the disease after his co-worker, Alois Alzheimer.

Alzheimer Disease↗
PubMed1997

Association of the mitochondrial tRNA(A4336G) mutation with Alzheimer's and Parkinson's diseases.

Alzheimer's and Parkinson's diseases (AD, PD) are among the most common neurodegenerative disorders in adults. Both AD and PD have a complex aetiology, and it is widely considered that genetic factors, acting independently or in concert with other genetic and/or environmental factors, modify the risk of developing them. While the apolipoprotein E (ApoE) epsilon 4 allele represents an established risk factor for familial and sporadic late-onset AD, it has been suggested that a common polymorphism in the alpha 1-antichymotrypsin gene modifies the ApoE epsilon 4 dosage effect in AD. Moreover, it has been proposed that a mitochondrial tRNA(Gln) sequence variant (A4336G transition) confers an increased risk for both AD and PD. This finding is of particular interest as the A4336G mutation seems to predispose to two clinically and neuropathologically distinct neurodegenerative disorders. We have examined the allelic frequencies of these putative susceptibility genes in 28 neuropathologically confirmed cases of AD, 23 cases with Lewy-body PD and 100 age-matched controls without clinical or histological evidence of neurodegenerative disease. The ApoE epsilon 4 allele frequency was significantly overrepresented in AD patients vs controls (0.35 vs 0.11) but we could not find evidence for an association between the alpha 1-antichymotrypsin AA genotype, the ApoE epsilon 4 allele and AD. In contrast, the mtDNA(A4336G) mutation was present in one of AD cases and in two of 23 PD patients, whereas no mutation was found in 100 age-matched controls (P < 0.05). Our data therefore support the hypothesis that the mitochondrial A4336G mutation represents a risk factor for AD and PD.

Aged↗
PubMed1996

The apolipoprotein E epsilon 4 allele in Parkinson's disease with Alzheimer lesions.

The association between the apolipoprotein E (ApoE) epsilon 4 allele and Parkinson's disease (PD) with coexistent dementia has remained controversial. We determined ApoE allele frequencies in 35 subjects with neuropathologically confirmed Lewy body Parkinsonism with and without concomitant Alzheimer lesions, 27 patients with Alzheimer's disease (AD), and 54 controls without neurodegenerative disease. We hypothesized that if AD lesions in PD evolve by the same pathomechanism as in "pure AD," the ApoE epsilon 4 allele frequency in PD with AD lesions (PD+AD) and pure AD should be similar. The frequency of the ApoE epsilon 4 allele differed significantly between PD+AD (13.3%) and AD cases (35.2%), but not between PD+AD and PD without AD pathology (12.5%) or controls (11.1%). We conclude that the ApoE epsilon 4 allele does not function as a risk factor which influences the development of AD lesions in PD. Our data suggest that Parkinson's disease with Alzheimer lesions and Alzheimer's disease with coexistent Parkinsonian features represent two distinct entities at both the clinicopathological and molecular genetic levels.

Aged↗
PubMed1996

Mitochondrial NADH dehydrogenase and CYP2D6 genotypes in Lewy-body parkinsonism.

The cause of nerve-cell death in sporadic Parkinson's disease remains unknown. Although environmental factors have been traditionally implicated in the etiology of Parkinson's disease, recent studies strongly suggest that there is a genetic contribution to this multifactorial disorder. We studied archival brain tissue from clinically and neuropathologically verified cases of Parkinson's disease, using nonradioactive cycle sequencing and restriction enzymatic analysis of polymerase chain reaction products. Twenty-one Parkinsonian brains with brain stem Lewy-bodies and 77 control brains were genotyped at two mitochondrial loci previously implicated in the etiology of neurodegenerative disease. In addition, genotyping was performed for two alleles of the debrisoquine 4-hydroxylase gene (CYP2D6). A heteroplasmic mtDNAG5460A missense mutation in the ND2 subunit gene of NADH dehydrogenase was three times more frequent in Parkinson cases (4/21) compared to controls (5/77). A homoplasmic mtDNAA4336G transition which alters the mitochondrial tRNAGln gene product was found in one Parkinson case. Frequencies of the CYP2D6G1934A and CYP2D6C2938T alleles were not significantly different between Parkinson cases and controls. Two Parkinsonian brains with high degrees of heteroplasmy for the ND2G5460A mutation and one CYP2D6C2938T homozygous case showed very high numbers of Lewy-bodies in the substantia nigra. The results of this study are in line with the concept that different genetic loci may be involved in Parkinson's disease susceptibility. They provide a hint that the ND2(5460) mutation, in combination with other factors, could play a role in disease pathogenesis in a subset of patients.

Aged↗
PubMed1995

Absence of the mitochondrial A7237T mutation in Parkinson's disease.

In recent years much has been speculated about a pathogenic role of mitochondrial defects in Parkinson's disease. Ozawa et al. (BBRC 176, 938-946, 1991) have described an A/T transversion at nucleotide 7237 of mitochondrial DNA affecting cytochrome-c-oxidase (complex IV) of the respiratory chain that could contribute to the pathogenesis of PD. Employing PCR based genomic sequencing and restriction enzyme analysis on 19 cases of Lewy-body parkinsonism, we exclude this mutation as a common cause of Parkinson's disease. This demonstrates the need for systematic sequencing of the mitochondrial genome in a large number of histologically verified cases of Parkinson's disease.

Adenine↗
PubMed1995

Apolipoprotein E genotype and neuropathological phenotype in two members of a German family with chromosome 14-linked early onset Alzheimer's disease.

Molecular genetic analysis was performed in two autopsy-confirmed cases of early-onset Alzheimer's disease belonging to a large German pedigree [FAD2, according to the nomenclature of St. George-Hyslop, et al. (1987) Science 235:885-890]. The disease in this family has been linked to chromosome 14. As gene interactions are considered to influence the age of onset and tissue pathology in Alzheimer's disease, we have studied three candidate genes that could modify disease progression. In this study a new polymerase chain reaction (PCR) assay was established for apolipoprotein E genotyping in archival neuropathological tissue, exon 17 of the amyloid precursor protein gene was directly sequenced, and a candidate mutation site at nucleotide (nt) 5460 of the mitochondrial NADH dehydrogenase subunit gene ND2 was analyzed employing PCR followed by HphI digestion. Whereas no sequence variations were detected in exon 17APP or at nt5460 of mitochondrial DNA, the apolipoprotein E genotypes of the two cases differed. Neuropathological examination revealed a higher number of beta A4-positive amyloid plaques and a larger total tissue area covered by beta A4 deposits in the epsilon 3/epsilon 3 homozygote. In contrast, the number of cortical neurofibrillary tangles and the number of plaques with tau-positive neurites appeared to be higher in the epsilon 3/epsilon 4 heterozygote. Our findings support the view that the chromosome 14 genetic defect, rather than apolipoprotein E genotype, is the preeminent factor determining Alzheimer's disease pathology in this family.

Alzheimer Disease↗
PubMed1994

No association of mutations at nucleotide 5460 of mitochondrial NADH dehydrogenase with Alzheimer's disease.

NADH dehydrogenase (EC 1.6.99.3) mutations at nucleotide 5460 of mitochondrial DNA (codon 331 of the ND2 subunit gene) have been associated with Alzheimer's disease (BBRC 182, 238-246, 1992; BBRC 189, 1202-1206, 1992). We have sequenced codons 304-347 of this gene in 15 neuropathologically confirmed cases of Alzheimer's disease. In addition, restriction enzyme analysis was performed on the same cases and on 28 control brains. No mutations were detected in the Alzheimer brains but heteroplasmy for a G-->A transition at nucleotide 5460 of mtDNA was found in the frontal cortex of a single control. Thus, our findings do not confirm reports of a significant association between mutations at nucleotide 5460 of mitochondrial DNA and Alzheimer's disease.

Aged↗
PubMed1994

Use of neuropathological tissue for molecular genetic studies: parameters affecting DNA extraction and polymerase chain reaction.

Nuclear and mitochondrial DNA were extracted from gray matter of human cerebral cortex which had either been formalin-fixed and embedded into paraffin or stored in formalin for up to 26 years. Extraction conditions were optimized for proteinase K digestion, i.e., enzyme concentration, digestion temperature and incubation time. Using the polymerase chain reaction (PCR), DNA was successfully amplified from archival material and sequenced employing a direct nonradioactive cycle sequencing protocol. In general, tissue embedded into paraffin following brief fixation in formalin gave good quantitative results, i.e., up to 1 microgram DNA/mg tissue were extracted. This yield was at least one order of magnitude higher than that obtained with tissue stored in formalin. However, paraffin-embedded neuropathological material was found to contain an as-yet-unidentified PCR inhibitor, and a deleterious effect of long-term fixation in unbuffered low-grade formalin was clearly detectable. Importantly, both paraffin-embedded tissue blocks and human brain that had been stored in formalin for many years yielded DNA sufficient for qualitative analysis. The implications of these findings for the use of neuropathological material in molecular genetic studies are discussed.

Aged↗
PubMed1993

Purification of human microsomal liver glucose-6-phosphatase system by affinity chromatography and immunodetection.

A multiple purification of phosphohydrolase (PH) and phosphotranslocase (PT) of the human liver microsomal glucose-6-phosphatase system has been obtained by a rapid two-step procedure using affinity chromatography. Sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) of the final products showed one major band each at 63 and 37 kDa for PH and PT respectively. The immunoblot analysis of SDS-PAGE of various purification steps for human liver using rabbit antibodies raised against the enzyme preparations also showed major bands at 63 and 37 kDa for PH and PT respectively. A major band at 260 kDa was observed by the Western blot of native PAGE of the enzyme preparation for PH. Cross-reacting materials at the positions of 63 and 37 kDa were detected only in liver, kidney and intestine. From five liver samples of patients suffering from type Ia glycogenosis there were diminished amounts of crossreacting materials at 63 kDa only in two samples. The uptake of glucose-6-phosphate has taken place in liposomes of Sepharose affinity purified products suggesting that this preparation may be a complex of PH and glucose-6-phosphate translocase.

Chromatography, Affinity↗
PubMed1993

Non-radioactive direct sequencing of PCR products amplified from neuropathological specimens.

We have developed a simple, rapid and relatively inexpensive protocol for direct non-isotopic cycle sequencing of DNA amplified using the polymerase chain reaction (PCR). PCR is performed on routine and archival neuropathological tissue. For sequencing, a 5'-digoxigenin end-labelled oligonucleotide primer is annealed and extended during thermal cycling, sequencing reactions are separated on a standard sequencing gel and the gel is contact-blotted to a nylon membrane. Sequenced DNA is visualized using immunological detection of digoxigenin.

Base Sequence↗
PubMedDate not supplied

Role of mitochondria in Parkinson disease.

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.

Apoptosis↗
PubMedDate not supplied

Regional heterogeneity of mtDNA heteroplasmy in parkinsonian brain.

There is increasing evidence for a role of defects of mitochondrial DNA in the etiology of neurodegenerative disorders such as Parkinson's and Alzheimer's disease as well as in normal aging. In several studies a biochemical defect of complex I of the respiratory chain (NADH dehydrogenase, EC 1.6.5.3) has been found in the substantia nigra of Parkinsonian brains. Thus, mutations of mitochondrial genes encoding subunits of complex I could contribute to the pathogenesis of Parkinson's disease. A heteroplasmic G5460A mutation affecting the ND2 subunit of NADH dehydrogenase was detected in several brains of patients with idiopathic Parkinson's disease. Since this mutation is heteroplasmic we were interested in the distribution of mutated and wild-type mitochondrial DNA in different brain areas. Relative levels of mutated DNA were quantified in a large number of anatomical regions using DNA extracted from formalin-fixed and paraffin-embedded brain tissue. DNA was amplified by the polymerase chain reaction and digested employing the restriction enzyme Hphl. The proportion of mutated DNA was determined by laser densitometry. In addition, genotype-phenotype analyses were performed on sections of the substantia nigra with the aid of an automated image analysis system. Ratios of mutant to wild-type DNA varied between 44% and 98%. However, there was no systematic relationship between mutated DNA ratios and ontogenetically related brain areas suggesting that the observed regional heterogeneity of mitochondrial DNA heteroplasmy is most likely due to random segregation during development. Therefore, tissue-specific differences in the sensitivity to pathogenic effects of the ND2(5460) mutation or the influence of additional susceptibility genes may be envisioned.

Brain↗