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Biomedical subjects

M B Graeber

Publications and source records attributed to M B Graeber.

At least 55 records · Page 3Linked to original sources
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

Unscheduled DNA synthesis and mitochondrial DNA synthetic rate following injury of the facial nerve.

Unscheduled DNA synthesis (UDS) of nuclear DNA and mitochondrial (mt) DNA synthetic rates were determined autoradiographically in different cell types of the rodent brain 14 days after unilateral facial nerve transection. In addition to an increased synthetic rate of mtDNA in facial motoneurons 12 h after axotomy, a significant increase of UDS, i.e., DNA repair, and mtDNA synthesis were found in the regenerating facial nucleus 4 days after axotomy. Specificity of the observed labeling was confirmed by injection of 3H2O instead of [3H]thymidine. Using electron microscopic autoradiography, it was further shown that cytoplasmic labeling of neurons was mainly due to incorporation of radioactive label into mitochondria, indicating their subsequent multiplication by division. The observation that Northern blot signals for O6-alkylguanine-DNA-alkyltransferase mRNA from homogenized facial nuclei of both the axotomized and normal side remained unchanged over 14 days after axotomy indicated that the observed DNA-repair activity was not caused by endogenously produced alkylating agents. The combined presence of transiently increased UDS, enhanced mtDNA synthesis and elevated protein synthetic rates of regenerating motoneurons (as shown in the literature) suggests that free radicals produced by mitochondria in injured nerve cells could cause unspecific DNA damage followed by immediate repair.

Animals↗
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

Population control of microglia: does apoptosis play a role?

Brain lesions, even of the most subtle type, are accompanied by the activation of microglia, the main immune cells of the brain. Microglial cells dramatically increase in number through proliferation and adhere to the injured neurons, where they displace the synaptic input. After proliferation, microglia gradually migrate into the nearby parenchyma and appear to decrease in number. Here we examined the possible involvement of apoptosis in the regulation of the microglial cell number using Terminal transferase mediated d-UTP Nick End-Labelling (TUNEL). In vitro, cell death is a common phenomenon in microglial cell cultures, and is enhanced by the withdrawal of the mitogen, granulocyte-macrophage colony stimulating factor. In vivo, application of the TUNEL-reaction revealed TUNEL-positive microglia beginning at day 4, with a peak 7 days after transection of the facial nerve. Surprisingly, TUNEL-labelling in vivo was localized on the outer side of the nuclear membrane and in the microglial cytoplasm, with very little staining within the nucleus itself. These TUNEL-labelled cells also lacked other classic morphological signs of apoptosis, like membrane blebbing, chromatin condensation and apoptotic bodies. These data suggest that the regulation of post-mitotic microglia is not mediated by the classic pathway of apoptosis.

Animals↗
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↗
PubMed1996

Neurogenetic diseases: molecular diagnosis and therapeutic approaches.

A neurogenetic disorder is defined as a clinical disease caused by a defect in one or more genes which affect the differentiation and function of the neuroectoderm and its derivatives. Genetic findings in various neurogenetic disorders are discussed. Huntington disease, spinobulbar muscular atrophy, and the autosomal dominant cerebellar ataxias are examples of autosomal dominant disorders caused by the expansion of trinucleotides (CAG) within disease genes. The CAG expansions appear to result in a gain of gene function. Prenatal, presymptomatic, and differential diagnostic tests are based on the detection of the repeat expansions. Point mutations within disease genes result in many additional neurogenetic disorders. An autosomal dominant form of amyotrophic lateral sclerosis and various types of craniosynostotic syndromes are described. The mutations in the disease genes also appear to result in a gain of gene function. Molecular diagnosis in these disorders is based on the direct examination of the mutated gene by methods such as single-strand conformation polymorphism analysis, denaturing gradient gel electrophoresis, and direct DNA sequencing. In many neurogenetic disorders the disease gene has not yet been identified. Here molecular diagnosis relies on indirect approaches based on methods such as the analysis of linkage and of allelic association. Hereditary forms of dystonia are presented as examples. Common sporadic neurological disorders such as Alzheimer and Parkinson diseases frequently have multifactorial causes. Investigations into the molecular basis and the development of diagnostic tests in these two important diseases are discussed. At present no curative therapies exist in neurogenetic disorders. Gene therapeutic approaches, however, provide promise for a cure in at least some of these diseases. Basic principles of gene therapy are explained and attempts at gene therapy in Alzheimer and Parkinson diseases are described. Finally, some of the many obstacles are summarized that must be overcome before gene therapy becomes feasible in most monogenic neurological diseases.

Genetic Diseases, Inborn↗
PubMed1996

Apolipoprotein E epsilon 4 allele, cognitive decline, and deterioration of everyday performance in Alzheimer's disease.

Many studies have demonstrated an association between the apolipoprotein E (apoE) epsilon 4 allele and Alzheimer's disease (AD). The present study is concerned with the relationship between the apoE epsilon 4 allele and the progression of symptoms in AD. We determined rates of cognitive decline and deterioration in everyday performance prospectively over 3 years in 64 patients with clinically diagnosed AD using the Cambridge Cognitive Examination (CAMCOG), the Mini-Mental State Examination (MMSE), and the Dementia Scale (DS) included in the Cambridge Mental Disorders of the Elderly Examination (CAMDEX). Carriers and noncarriers of the epsilon 4 allele did not significantly differ in cognitive functioning and everyday performance at baseline measurements. The time that had elapsed since the estimated onset of symptoms was also not different between the two groups. This suggested that the clinical progression of AD was not associated with the epsilon 4 status before the patients entered the study. On prospective observation, the rate of cognitive decline assessed with the CAMCOG and the MMSE and the rate of deterioration in everyday performance rated with the DS were also not different between carriers and noncarriers of the epsilon 4 allele. We conclude that the clinical course of AD is independent of the apoE epsilon 4 allele.

Age of Onset↗
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↗
PubMed1994

Molecular basis and diagnosis of neurogenetic disorders.

Over the past few years, molecular neurogenetics has developed into one of the most promising and active research fields. The new discipline applies modern molecular genetic techniques to the investigation of classical neurological disorders. In the following article, a definition of neurogenetic disease is introduced, the molecular basis of four groups of neurogenetic disorders is described and recent diagnostic developments are presented. The first group of diseases is caused by trinucleotide expansions. "Expanding" trinucleotide repeats were not known to occur in any species until about three years ago. Today, disorders such as Huntington's disease, spinocerebellar ataxia type 1, fragile X mental retardation, spinobulbar muscular atrophy and myotonic dystrophy are all known to be caused by the expansion of trinucleotides. The second group is characterized by chromosomal deletions or uniparental disomies. Lissencephaly and the Miller-Dieker syndrome, Prader-Willi and Angelman syndromes and Duchenne and Becker muscular dystrophies belong to this category. The third group includes those neurogenetic disorders that are mainly caused by point mutations such as the X-linked leukodystrophies, including Pelizaeus-Merzbacher disease and adrenoleukodystrophy, Charcot-Marie-Tooth syndrome type 1, familial forms of amyotrophic lateral sclerosis, several types of craniosynostoses and some CNS tumor syndromes. Finally, Alzheimer's and Parkinson's disease are discussed as representatives of group four, i.e. genetically heterogeneous neurological disorders.

Animals↗