Biomedical subjects

P Mehraein

Publications and source records attributed to P Mehraein.

At least 19 recordsLinked to original sources

PubMed2001

Apoptosis in the basal ganglia of the developing human nervous system.

Programmed cell death (PCD) plays a crucial role in the development of the central nervous system through controlling neuronal numbers and adequate synaptic connections. PCD has been considered to occur in the form of apoptosis. To examine how apoptosis occurs in the developing human brain, we performed a morphometric TUNEL study, using a commercially available kit (ApopTag Kit, Oncor Inc.). We examined apoptotic cells in the basal ganglia of 47 fetuses and newborns without macroscopical and microscopical evident congenital anomalies. Gestational age ranged from 12 to 40 weeks. The numerical density as well as the labeling index of TUNEL-positively labeled nuclei were evaluated. In the caudate nucleus and putamen, TUNEL-labeled cells were observed around the 12th week of gestation. The numerical density of total cells was significantly decreased, whereas the labeling index of apoptotic cells was significantly increased with advanced gestational age. In the globus pallidus, the numerical density of total cells decreased with advancing gestational age, while the labeling index of apoptotic cells increased between the 20th and 28th week, followed by a decrease until the 40th week. The analysis of TUNEL-positive cells revealed a different reaction pattern for the various basal ganglia with regard to the timing and degree of the apoptotic process in regulating cell numbers.

Age Factors↗

PubMed2000

Neuronal damage of the substantia nigra in HIV-1 infected brains.

Extrapyramidal motor disorders are frequently noted in HIV-1-infected patients. In the present study, the substantia nigra was analyzed morphometrically to detect neuronal changes which might contribute to the pathogenetic mechanisms causing extrapyramidal motor dysfunction in HIV-1-infected patients. The numerical density and the size of pigmented, non-pigmented small, and non-pigmented large neurons in four nuclei of the substantia nigra pars compacta (antero-medial, antero-intermediolateral, postero-lateral, and postero-medial nuclei) in HIV-1-infected patients and in age-matched normal controls were determined. In HIV-1-infected brains, the numerical density of total neurons (i.e., pigmented and non-pigmented) as well as of pigmented neurons was significantly decreased, whereas that of non-pigmented neurons was not significantly changed in all investigated nuclei of the substantia nigra as compared to normal controls. A specific pattern of increase and decrease of nonpigmented large and non-pigmented small neurons was observed. The size of total neurons (pigmented and nonpigmented neurons) and of pigmented neurons was significantly reduced in all investigated nuclei of HIV-1-infected brains. The results suggest that neuronal degeneration in the substantia nigra commonly occurs and may be related to extrapyramidal symptoms in HIV-1-infected patients.

AIDS Dementia Complex↗

PubMed1999

Analysis of mitochondrial targeting sequence and coding region polymorphisms of the manganese superoxide dismutase gene in German Parkinson disease patients.

Two polymorphisms of the MnSOD gene, Ile58Thr and Ala9Val, have been associated with Parkinson disease (PD). The Ile58Thr amino acid exchange affects the stability at the tetrameric interface of the enzyme and reduces the enzymatic activity of MnSOD while the Ala/Val substitution at position -9 of the mitochondrial targeting sequence (MTS) may lead to misdirected intracellular trafficking. We have analyzed 63 German Caucasian PD patients for possible sequence variation in the MTS as well as in exon 3 of the MnSOD gene. All 63 PD patients analyzed exhibited a T at nucleotide position 5777 in exon 3 of the MnSOD gene corresponding to ATA, or Ile at the peptide level, and no other sequence variants were found. In addition, both alleles of the Ala9Val polymorphism in the MTS of MnSOD were equally distributed between German PD patients and controls excluding this gene variant as a risk factor for PD in Caucasian subjects.

Aged↗

PubMed1999

Reanalysis of the first case of Alzheimer's disease.

When a disease becomes as important as Alzheimer's dementia, there is a natural interest in its medical history and in the origin of the underlying disease concept. Key to understanding Alois Alzheimer's views on the disease, which was named after him, are the histological sections of the cases he saw. This histological material was rediscovered in Munich in 1992 and 1997 (Neurogenetics 1997, 1:73-80; 1998, 1:223-228). An extensive neuropathological and molecular genetic analysis of the tissue is currently being carried out. The present article summarizes the history of the rediscovery and provides an analysis of the neuropathology of Alois Alzheimer's first case, Auguste D.

Alzheimer Disease↗

PubMed1999

The alpha1-antichymotrypsin A-allele in German Parkinson disease patients.

An increased frequency of the A-allele of the alpha-antichymotrypsin (ACT) gene has been recently described in Japanese patients suffering from Parkinson disease (PD). In the present study, we have analyzed 62 German PD patients with regard to their ACT and APOE genotypes and compared them to 53 controls without clinical or pathological evidence of neurodegenerative disease. The A-allele frequency was 47% in PD patients compared to 54% in control cases excluding ACT as a major susceptibility factor for PD in the Caucasian population. Yet, ACT-A allele frequencies were significantly different (p < 0.001) between Japanese and German controls. Therefore, although our data do not suggest that the alpha1-ACT polymorphism is a significant risk factor for the development of PD, a consideration of differences in genetic background seems warranted when evaluating susceptibility factors for neurodegenerative disease.

Aged↗

PubMed1999

Two novel point mutations of mitochondrial tRNA genes in histologically confirmed Parkinson disease.

Mutations in mitochondrially encoded tRNA genes have been described in a variety of neurological disorders. One such mutation, the A to G transition at nucleotide position 4336 of the mitochondrial tRNA(Gln) gene, has been associated with both Alzheimer and Parkinson disease. We have now performed a complete sequence analysis of all 22 mitochondrially encoded tRNA genes in 20 cases of histologically proven idiopathic Parkinson disease. Genomic DNA extracted from the substantia nigra of frozen or formalin-fixed and paraffin-embedded brains was used for amplification by polymerase chain reaction followed by automated sequencing. Two new homoplasmic point mutations were detected in the genes for tRNA(Thr) (15950 G/A) and tRNA(Pro) (15965 T/C) in 1 patient each. Restriction enzyme digestion revealed absence of the 15950 G/A mutation in 96 controls and in 40 cases of neuropathologically confirmed Alzheimer disease. The 15965 T/C mutation was shown to be absent from 100 control subjects and 47 Alzheimer cases. In addition to the two novel mutations, six known sequence variants were detected in a total of 6 different patients in the genes for tRNA(Asp) (G7521A, 1), tRNA(Arg) (T10463C, 1), tRNA(LeuCUN) (A12308G, 2), and tRNA(Thr) (A15924G, 1; G15928A, 2), including 1 patient carrying the tRNA(Gln) (A4336G) mutation. The G15950A transition affects position 70 of the aminoacyl acceptor stem of tRNA(Thr), which has been implicated as a recognition element for threonyl-tRNA synthetase and, at least in some tRNAs, in the processing of primary mitochondrial transcripts. The T15965C point mutation in the mitochondrial tRNA(Pro) gene alters position 64 of the TpsiC stem. The corresponding nucleotide in bacterial aminoacyl-tRNAs is involved in the interaction with elongation factor Tu. Thus, the two novel mutations are likely to be of functional relevance and could contribute to dopaminergic nerve cell death in affected individuals.

Aged↗

PubMed1998

Novel mutations of mitochondrial complex I in pathologically proven Parkinson disease.

Complete sequence analysis of all mitochondrial complex I genes was performed in 22 cases of neuropathologically confirmed idiopathic Parkinson disease (PD). DNA from the substantia nigra was used as a template for polymerase chain reaction-based genomic sequencing. Seven novel mutations causing the exchange of amino acids were detected in subunit genes ND1 (3992 C/ T, 4024 A/G), ND4 (11253 T/C, 12084 C/T), ND5 (13711 G/A, 13768 T/C), and ND6 (14582 T/C). In addition, five known missense mutations affecting the ND1 (3335 T/C, 3338 T/C), ND2 (5460 G/A), ND3 (10398 A/G), and ND5 (13966 A/G) genes as well as three secondary LHON mutations (4216 T/C, 4917 A/ G, 13708 G/A) were found in the PD group. Among the novel mutations, the 11253 T/C transition which changes a conserved isoleucine residue into threonine is most likely to be of functional relevance. Furthermore, 43 synonymous polymorphisms were detected in PD brains, including 20 novel sequence variants. Haplogroup analysis revealed that most unique missense mutations were found in PD cases belonging to the D(c) haplogroup. Our data are in line with the view that PD is not a single disease entity but comprises a genetically heterogeneous group of disorders. The results of our study further suggest that 90% or more of all idiopathic PD cases are not due to sequence variation of mitochondrial complex I, but that mitochondrial mutations may play a pathogenic role in a subset of PD patients.

Aged↗

PubMed1998

Histopathology and APOE genotype of the first Alzheimer disease patient, Auguste D.

Alois Alzheimer published two papers on the disease which was named after him by Emil Kraepelin in 1910. Each of these papers contains clinical and pathological data on a patient Alzheimer had seen at the hospital. We have previously reported on the rediscovery of tissue sections from Alzheimer's second published case of Alzheimer disease, Johann F., which probably gave the disease its name (Neurogenetics 1997; 1:73-80). Here, we describe the histopathology and APOE genotype of Alois Alzheimer's first patient, Auguste D. As in the case of Johann F., a large number of tissue sections belonging to Alzheimer's laboratory, which was later headed by Spielmeyer, were found among material kept at the Institute of Neuropathology of the University of Munich. As described by Alzheimer in his original report (Allg Zeitschr Psychiatr 1907; 64:146-148), there were numerous neurofibrillary tangles and many amyloid plaques, especially in the upper cortical layers of this patient. Yet, there was no microscopic evidence for vascular, i.e., arteriosclerotic, lesions. Interestingly, Alzheimer's histological preparations did not include the hippocampus or entorhinal region. The APOE genotype of this patient was shown to be epsilon3/epsilon3 by PCR-based restriction enzyme analysis, indicating that mutational screening of the tissue is feasible. The historical importance of the case of Auguste D. lies in the fact that it marks the beginning of research into Alzheimer disease. In addition, neurofibrillary tangles were first described in this brain.

Alzheimer Disease↗

PubMed1998

Differential expression of MHC class II molecules by microglia and neoplastic astroglia: relevance for the escape of astrocytoma cells from immune surveillance.

There is increasing evidence that microglia serve as antigen presenters in the human CNS. Although the occurrence of MHC class II immunoreactive cells has been reported in astrocytic gliomas, the relative contribution of microglia to this cell population has not been studied in detail. Using computer-assisted image analysis, we have investigated the expression of MHC class II molecules and of the microglia/macrophage markers Ki-MIP, RCA-1, KP1 and iba1, in 97 astrocytic gliomas comprising all WHO grades to answer the question whether there is a correlation between tumour grade and the number of MHC class II positive microglia/macrophage profiles. Microglia expressing MHC class II were common in astrocytomas and anaplastic astrocytomas but rare in pilocytic tumours although there was significant variation within each group. MHC class II immunoreactivity was reduced in highly cellular areas of glioblastomas where large numbers of cells expressing macrophage markers were still present. Thus, there was no simple relationship between tumour grade and microglial/macrophage MHC class II expression. In addition, up to 55% of astrocytic gliomas contained MHC class II immunoreactive tumour cells. Microglia but not tumour cells were found to express the BB1/B7 costimulator. We conclude that microglia in astrocytic gliomas are well equipped to function as antigen presenting cells. Yet, neoplastic astroglia appear to acquire the capacity to downregulate microglial MHC class II expression and, at the same time, may induce T-cell clonal anergy through aberrant expression of MHC class II molecules.

Antigen Presentation↗

PubMed1998

Microglia and the development of spongiform change in Creutzfeldt-Jakob disease.

Recent in vitro experiments suggest that neurotoxicity of the prion protein is dependent on the presence of microglia. We have studied 11 cases of Creutzfeldt-Jakob disease (CJD) using immunocytochemistry in combination with computerized image analysis to clarify the relationship between spongiform change and microglial activation. MHC class II-positive microglia were almost exclusively confined to cortical gray matter where the neuropil area occupied by these cells exceeded that of controls more than 350-fold. In cortical regions with a bimodal distribution of spongiform degeneration, the presence of class II-positive microglia correlated well with the presence of vacuolation in layer V, but significantly less with spongiform change in layers II and III. In areas where spongiform degeneration affected the entire depth of the cortex, activated microglia were predominantly located in the inner one-half of the cortex or were evenly distributed throughout all cortical laminae. Here, microglia exhibited atypical, tortuous cell processes and occasionally intracytoplasmic vacuoles, suggesting that microglia themselves may become a disease target. Taken together, our results provide indirect evidence against an early causative involvement of microglia in the development of spongiform change. At later stages, however, diseased microglia could produce harmful factors which mediate both astrogliosis and neuronal injury.

Aged↗

PubMed1997

Defects of cytochrome c oxidase in the substantia nigra of Parkinson's disease: and immunohistochemical and morphometric study.

Defects of respiratory chain complexes were considered as possible pathogenetic mechanisms in Parkinson's disease (PD). Changes of cytochrome c oxidase (COX) in four different nuclei of the substantia nigra of 8 PD cases and 10 age-matched controls were investigated by means of morphometry and immunohistochemistry. Pigmented neurons with COX defects were randomly distributed within the the four nuclei of PD cases, but only in the posterolateral nucleus was the numerical density of pigmented neurons with COX defects significantly increased compared with controls. The numerical density of pigmented neurons without COX defects was significantly reduced in the anteromedial, anterointermediolateral, and posterolateral nuclei in PD. The cell size of pigmented neurons with and without COX defects was significantly diminished in the anteromedial and posterolateral nuclei of PD cases. It is suggested that complex IV defects in nigral neurons are most probably a result of accelerated aging, but are least likely to be a primary aspect of the pathogenetic processes occurring in PD.

Aged↗

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

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↗

PubMed1996

Vascular changes in the cerebral cortex in HIV-1 infection. II. An immunohistochemical and lectinhistochemical investigation.

In human immunodeficiency virus 1 (HIV-1)-infected patients, a hypoperfusion is seen by SPECT analyses in different brain regions but a specific pattern for the predominance of a specific brain region has not been found. The vessels of the cerebral cortex of the frontal, temporal, parietal, and occipital lobes of acquired immunodeficiency syndrome (AIDS) brains and control brains were analyzed by immunohistochemistry and lectin histochemistry. Immunohistochemistry was performed for collagen IV, laminin (basal lamina), and factor VIII (endothelial cell) and lectin histochemistry [Ricinus communis agglutinin (RCA-I), Ulex europaeus agglutinin (UEA-I), wheatgerm agglutinin (WGA) and soybean agglutinin (SBA)] was used to study changes of glycoproteins in the endothelial cell membrane. Vessels were counted in the gray and white matter, and their staining intensity for the different antibodies and lectins was rated using a three-point scale. Immunoreactivity for collagen IV was reduced in AIDS brains, which may be related to thinning of the basal lamina of cerebral vessels, as has previously been shown by electron microscopy. Lectin histochemistry with SBA, UEA-I and WGA indicated loss of glycoproteins in the membrane of endothelial cells. The data from the present study show morphological changes of the endothelial cells and of the basal lamina in the brain of individuals with AIDS, and might represent the morphological sequelae of a disturbed blood-brain barrier, or may account for the hypoperfusion seen in SPECT analyses.

Acquired Immunodeficiency Syndrome↗