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Biomedical subjects

A Mannermaa

Publications and source records attributed to A Mannermaa.

At least 55 records · Page 3Linked to original sources
PubMed1996

Apolipoprotein E polymorphism in patients with different neurodegenerative disorders.

Apolipoprotein E (ApoE) is associated with Alzheimer's disease (AD) neurofibrillary tangles and beta-amyloid protein in senile plaques. There are three common alleles of ApoE, designated epsilon 2, epsilon 3 and epsilon 4. We studied Finnish patients with neurodegenerative disorders: AD, vascular dementia (VAD), Parkinson's disease (PD), PD+dementia (PDD), Lewy body variant of AD (LB), frontal dementia (FD), and Down's syndrome (DS), as well as control individuals (C). The ApoE genotypes and corresponding allele frequencies of 188 patients and 60 controls were determined by digestion of ApoE polymerase chain reaction products with the restriction enzyme Hha I. The ApoE epsilon 4 allele frequency was 0.17 for C, 0.44 for AD, 0.35 for VAD, 0.10 for PD, 0.38 for PDD, 0.28 for LB, 0.39 for FD, and 0.17 for DS. We found significant differences in genotype frequency between AD/C, AD/PD and AD/DS. Our results suggest that, beside AD, an increased frequency of epsilon 4 may also be involved in other dementing neurological disorders.

Adult↗
PubMed1996

SPECT and MRI analysis in Alzheimer's disease: relation to apolipoprotein E epsilon 4 allele.

OBJECTIVES: The epsilon 4 allele of apolipoprotein E (ApoE) is a risk factor for late onset Alzheimer's disease. ApoE is present in senile plaques, neurofibrillary tangles, and cerebrovascular amyloid, and it is implicated in synaptogenesis. The effect of ApoE polymorphism on the volumes of hippocampus, amygdala, and frontal lobe was studied. The hypothesis was that the patients with Alzheimer's disease carrying the epsilon 4 allele have more pronounced atrophy. The relation of ApoE and cerebral blood flow on cortical areas was also assessed. METHODS: Fifty eight patients with Alzheimer's disease at the early stage of the disease and 34 control subjects were studied. Patients with Alzheimer's disease were divided into subgroups according to the number of the epsilon 4 alleles. Volumes were measured by MRI and regional cerebral blood flow ratios referred to the cerebellum were examined by 99mTc-HMPAO SPECT. ApoE genotypes were determined by digestion of ApoE polymerase chain reaction products with the restriction enzyme Hha1. RESULTS: patients with Alzheimer's disease had smaller volumes of hippocampi and amygdala compared with control subjects, and the patients with Alzheimer's disease homozygous for the epsilon 4 allele had the most prominent volume loss in the medial temporal lobe structures. The frontal lobe volumes did not differ significantly. All patients with Alzheimer's disease had bilateral temporoparietal hypoperfusion and the subgroups with one or no epsilon 4 alleles also had frontal hypoperfusion compared with control subjects. The occipital perfusion ratios tended to decrease with increasing number of epsilon 4 alleles. CONCLUSIONS: Patients with Alzheimer's disease homozygous for the epsilon 4 allele seem to have severe damage in the medial temporal lobe structures early in the disease process and differ from the patients with Alzheimer's disease with one or no epsilon 4 alleles.

Age of Onset↗
PubMed1996

Clinical and neuropsychological characteristics in familial and sporadic Alzheimer's disease: relation to apolipoprotein E polymorphism.

Alzheimer's disease (AD) is a heterogeneous entity presenting as sporadic and familial disease. In familial AD, there is evidence for genetic linkage to a yet undefined gene on chromosome 14 in early-onset pedigrees and on chromosome 19 in late-onset pedigrees. In a few early-onset kindreds, there were mutations in the amyloid precursor gene on chromosome 21. There is an increased frequency of apolipoprotein E (ApoE) epsilon4 allele in patients with late-onset AD. We studied the clinical presentation and profile of cognitive deficits in 58 AD patients at the early stage of the disease. We divided the AD patients into subgroups of sporadic late-onset (SLO) (> or = 65 years), familial late-onset (FLO) (> or = 65 years), sporadic early-onset (SEO) (<65 years), and familial early-onset (FEO) (<65 years) patients and into three subgroups according to their ApoE genotype zero epsilon4, one epsilon4, and two epsilon4 alleles. The AD subgroups did not differ in the global clinical severity of dementia or the duration of the disease. SLO, FLO, SEO, and FEO subgroups did not differ in clinical characteristics such as occurrence of rigidity, hypokinesia, tremor, myoclonus, hallucinations, delusions, or epileptic seizures nor in the profile of deficits on tests assessing memory, language, visuospatial, executive, and praxic functions. The epsilon4++ allele frequency was 0.43 for all AD patients and did not differ across subgroups divided according to the familial aggregation and age of onset. Patients with two epsilon4 alleles had earlier age at onset of dementia than those with no epsilon4 allele (63 +/- 9 versus 68 +/- 9 years), but otherwise the clinical symptoms and signs were not related to the ApoE genotype. However, the AD patients with two epsilon 4 alleles had lowest scores on memory tests and differed significantly from those with one or zero epsilon4 allele in the delayed list learning (p<0.05) and from those with zero epsilon4 allele in the immediate and delayed story recall. In contrast, verbal functions were better preserved in two epsilon4 patients than in those with other ApoE genotypes. This study failed to confirm the earlier reports of severe aphasia, agnosia, and apraxia in familial AD patients, but the clinical phenotype was similar irrespective to the familial aggregation. However, AD patients with two epsilon4 alleles are characterized by more severe memory loss and earlier age of onset than those without the epsilon4 allele.

Age of Onset↗
PubMed1995

Loss of heterozygosity for chromosome 11 in primary human breast tumors is associated with poor survival after metastasis.

A common feature of the malignant progression of human tumors is loss of heterozygosity (LOH) for various regions of their genomes. Such events encompassing chromosomes 11p15 and 11q23 are frequent in human breast tumors. Here, we have analyzed genetic and clinical characteristics of a series of primary breast tumors in order to determine: (a) a more finely mapped estimate of the involved regions; (b) whether there is a relationship in the presentation of LOH between the two regions; and (c) whether a correlation exists between such LOH and any of the clinical parameters pertaining to each patient. We found that LOH for 11p15.5 and 11q23 occurred in 35 and 46% of the 86 primary breast carcinomas, respectively, but in none of the 10 benign tumors examined. The minimal region of LOH for 11p15 was in the approximately 2-megabase region between loci TH and D11S988. Twenty-nine % of the tumors showed LOH simultaneously at both 11p15 and 11q23, 5% had LOH only at 11p15.5, and 15% had LOH only at 11q23. Among these genetic groups, clinical features such as tumor size, involvement of auxiliary nodes, histological subtype, tumor grade, estrogen/progesterone receptor status, and patient age were not markedly different. However, LOH of 11q23 (either alone or in conjunction with LOH of 11p15) in the primary tumor was found to be highly predictive of aggressive postmetastatic disease course with substantially reduced survival (P = 0.0004; log rank test). We also observed a slight trend toward a more rapid development of metastatic lesions, without obvious site specificity, in patients with primary tumors showing LOH for chromosome 11 in the pathogenesis of human breast cancer; we suggest that its effects are late in the progression of this disease.

Breast Neoplasms↗
PubMed1995

A severe loss of choline acetyltransferase in the frontal cortex of Alzheimer patients carrying apolipoprotein epsilon 4 allele.

We measured the activities of choline acetyltransferase (ChAT) in the post mortem frontal cortex in 32 Alzheimer's disease (AD) patients with different apolipoprotein E (apoE) genotypes. The ChAT values were significantly lower for the AD patients with 2 epsilon 4 alleles than for those with 0 epsilon 4 (ANOVA, P < 0.05). The ChAT activities of AD patients carrying 2 or 1 epsilon 4 alleles and those without the epsilon 4 allele also differed significantly: 16.3 +/- 15.2 versus 30.5 +/- 20.6 pmol/mg protein per min, ANOVA, P < 0.05. However, the AD patients carrying the epsilon 4 allele were significantly younger than those with 0 epsilon 4 allele. The study indicates that AD patients carrying the epsilon 4 allele have a more severe cholinergic deficit than the AD patients without the epsilon 4 allele.

Aged↗
PubMed1995

Apolipoprotein E polymorphism and Alzheimer's disease in eastern Finland.

Apolipoprotein E is a polymorphic protein defined by three alleles, epsilon 2, epsilon 3 and epsilon 4. An increased frequency of the epsilon 4 allele is associated with late-onset familial and sporadic Alzheimer's disease (AD). We studied 202 Finnish AD patients and 55 age- and sex-matched controls. AD patients were divided into four subgroups; sporadic early-onset, sporadic late-onset, familial early-onset and familial late-onset disease. We found no significant differences in the epsilon 4 allele frequency between the subgroups. However, all the subgroups differed in the frequency of epsilon 4 allele detection from the controls (P < 0.0001). In the late-onset patients, the age at onset decreased from 76 to 69 as the number of epsilon 4 alleles increased from 0 to 2.

Age of Onset↗
PubMed1995

Carrier diagnosis of the fragile X syndrome--a challenge in antenatal clinics.

OBJECTIVE: The fragile X syndrome, a common cause of mental retardation, is poorly recognized even in families at risk. The aims of our study were to evaluate the possibility of finding previously unidentified carriers of the genetic defect in fragile X families, to use this information in antenatal diagnosis, and to study the attitudes of these families to genetic screening. STUDY DESIGN: We identified 59 fragile X families living in a population of 900,000 inhabitants. A deoxyribonucleic acid test on the FMR1 gene was offered to 1071 persons in these families who had a risk of at least 12.5% of having the fragile X premutation or full mutation. RESULTS: A total of 48.1% of the persons who were offered the test accepted it. A diagnosis was made in 20 male and 66 female subjects with the full mutation and in 30 male and 133 female subjects with a premutation. All 21 pregnant carriers of this mutation accepted chorionic villus biopsy. CONCLUSION: Pregnant relatives should be informed of the availability of screening for fragile X carrier status in families with a member having clinical fragile X syndrome. Antenatal clinics offer a good gateway for approaching families with this inherited developmental defect.

DNA Mutational Analysis↗
PubMed1995

Volumes of hippocampus, amygdala and frontal lobe in Alzheimer patients with different apolipoprotein E genotypes.

An increased frequency of apolipoprotein E E4 allele has been reported in patients with late onset Alzheimer's disease. Apolipoprotein E participates in the transport of cholesterol and other lipids and interferes with the growth and regeneration of both peripheral and central nervous system tissues during development and after injury. Apolipoprotein E is also implicated in synaptogenesis. Apolipoprotein E isoforms differ in binding to amyloid-beta-protein and tau protein in vitro. Here, we wanted to study the effect of apolipoprotein E genotype on the magnitude of damage in the hippocampus, where a marked synapse loss exists in Alzheimer's disease. We measured by magnetic resonance imaging the volumes of the hippocampus, amygdala, and frontal lobes in the three Alzheimer subgroups: patients with 2, 1 or 0 E4 alleles. We also investigated the profile of deficits on tests assessing memory, language, visuospatial, executive, and praxic functions of these Alzheimer subgroups. All Alzheimer patients were at early stage of the disease. We found that Alzheimer patients with E4/4 genotype (N = 5) had smaller volumes of the hippocampus and the amygdala than those with E3/4 (N = 9) and those with E3/3 or E2/3 (N = 12). The difference was significant for the right hippocampus (-54% of control) and the right amygdala (-37% of control). The volumes of the frontal lobes were similar across the Alzheimer subgroups. The patients with E4/4 also showed lowest scores on delayed memory tests and differed from E3/3, 3/2 patients in the list learning test (< 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1995

Relation of coronary atherosclerosis and apolipoprotein E genotypes in Alzheimer patients.

BACKGROUND AND PURPOSE: Apolipoprotein E (apoE) epsilon 4 allele has been associated with a high risk for coronary heart disease. Increased frequency of the epsilon 4 allele has also been reported in patients with late-onset familial and sporadic Alzheimer's disease (AD). The aim of this study was to investigate the degree of coronary and cerebral atherosclerosis in a neuropathologically verified series of AD patients with different apoE genotypes. In addition, we studied the relationship between the degree of coronary and cerebral atherosclerosis and the extent of beta-amyloid (A beta) accumulation. METHODS: We studied 38 subjects (32 patients with definite AD and 6 age-matched control subjects) for whom postmortem autopsy delay was less than 8 hours. ApoE genotypes were identified through Hha I digestion of the polymerase chain reaction-amplified samples. We used A beta immunohistochemistry to detect diffuse and neuritic plaques as well as cerebrovascular amyloid. The degree of coronary and cerebral atherosclerosis was rated as none, mild, moderate, or severe. RESULTS: The apoE genotypes of the AD patients were epsilon 4/4 2, epsilon 3/4 19, epsilon 3/3 9, and epsilon 3/2 2. We found more severe atherosclerosis of the coronary vessels among AD patients with the apoE epsilon 4 allele compared with those AD patients without the epsilon 4 allele (chi 2 = 4.1, df = 1, P < .05). The extent of cerebral atherosclerosis did not differ among AD subgroups with and without the epsilon 4 allele. The degree of coronary or cerebral atherosclerosis was not related to the amount of amyloid accumulation in the frontal and temporal cortices or in the hippocampal structures. CONCLUSIONS: This study confirms the association of apoE epsilon 4 allele with coronary atherosclerosis in AD patients.

Aged↗
PubMed1994

A point mutation in the putative TATA box, detected in nondiseased individuals and patients with hereditary breast cancer, decreases promoter activity of the 17 beta-hydroxysteroid dehydrogenase type 1 gene 2 (EDH17B2) in vitro.

EDH17B2, the gene encoding 17 beta-hydroxysteroid dehydrogenase type 1, has been suggested as a candidate for the familial breast cancer gene, BRCA1, located on 17q12-q21. We analyzed the promoter region of EDH17B2 in DNA from 20 control individuals and 40 patients with familial breast cancer. Two frequent (designated vI and vIII) and two rare (vII and vIV) nucleotide variations were present in both the breast cancer patients and the controls, except the alteration vII, which was found only in one patient. Although the data do not support the identification of EDH17B2 as the BRCA1 gene, it is of interest that point mutation vIV (A-->C) was located in the putative TATA box of the EDH17B2 gene. Reporter gene analyses showed that the mutation vIV decreases EDH17B2 promoter activity by an average of 45% in in vitro assays, suggesting that nucleotide A at position -27 is significant for efficient transcription.

17-Hydroxysteroid Dehydrogenases↗
PubMed1994

Loss of heterozygosity in sporadic human breast carcinoma: a common region between 11q22 and 11q23.3.

The development of sporadic human breast cancer is associated with the accumulation of genetic alterations on several chromosomes. In the case of chromosome 11, loss of heterozygosity (LOH) at loci on the short arm has been well documented and suggests the presence of a suppressor gene(s) at 11p15.5. However, the evidence for similar events on the long arm is less compelling. Here, we determined the prevalence of LOH for chromosome 11q in 44 malignant and 3 benign cases of unselected sporadic breast tumor samples. We found that alteration of chromosome 11q is common in the pathogenesis of breast cancer as 19 of 44 (43%) malignant tumor specimens exhibited LOH. Eleven (58%) of these genetic alterations were specific to the long arm of the chromosome. The smallest region of shared LOH places the target between 11q22 and 11q23.3, the same general region frequently altered in cancers of the ovary, colon, skin, and uterine cervix, perhaps indicating the location of a tumor suppressor gene or genes of importance in each of these different tumor types.

Breast Neoplasms↗
PubMed1994

Human familial and sporadic breast cancer: analysis of the coding regions of the 17 beta-hydroxysteroid dehydrogenase 2 gene (EDH17B2) using a single-strand conformation polymorphism assay.

17 beta-Hydroxysteroid dehydrogenase (17HSD) is one of the key enzymes in estrogen metabolism, catalyzing the reversible reaction between estradiol and the less active estrogen, estrone. The gene encoding this enzyme, EDH17B2, has been mapped to chromosome 17, region q12-q21, in the vicinity of BRCA1, as as yet unidentified gene that appears to be involved in familial breast cancer and in familial ovarian cancer. The possibility that EDH17B2 gene is the same as BRCA1 was tested by screening for mutations in the coding regions of EDH17B2, using a polymerase chain reaction/single-strand conformation polymorphism method. An A-->G transition creating a new BstUI site at exon 6 was the only frequent sequence alteration found in the coding region of the gene. This mutation also led to an amino acid substitution of serine to glycine at position 312 (312S-->312G) in the 17HSD protein. Since the nucleotide change was detected both in specimens from patients with familial or sporadic cancer and in control samples, and at similar rates, this mutation appears to be of a polymorphic nature. In addition, a rare polymorphism located at intron 5 was detected. This C-->T substitution creates a BbvI site and is not thought to have any effect on 17HSD activity. The results indicate that there are no major alterations in the coding areas of EDH17B2 and thus studies testing the hypothesis that EDH17B2 may be the same as BRCA1 should be extended to the promoter and regulatory elements of EDH17B2.

17-Hydroxysteroid Dehydrogenases↗
PubMed1994

Application of fine-needle aspiration to the demonstration of ERBB2 and MYC expression by in situ hybridization in breast carcinoma.

Thirteen consecutive fine-needle aspirates of breast carcinoma and five selected breast tumor cell lines were analyzed for ERBB2 and MYC mRNA expression by in situ hybridization. To compare the level of mRNA synthesis with those of gene amplification and oncoprotein synthesis, all tumors were also analyzed by Southern blot analysis, and for ERBB2 also by immunohistochemistry. Expression of ERBB2 mRNA was observed in eight tumors. MYC expression was observed in all tumors studied. Three tumor cell lines expressed both ERBB2 and MYC (SK-BR-3, HeLa, HT-29) and two only MYC (SK-LU-1, HL-60). Only one tumor showed amplification of ERBB2 and two of MYC. In all three cases there was a considerable increase in corresponding mRNA synthesis as detected by in situ hybridization. By immunohistochemistry, four cases showed either patchy areas or uniformly distributed, membrane-bound ERBB2 immunoreactivity. All except one case showed increased ERBB2 mRNA synthesis. There was a clear association between the quantity of ERBB2 mRNA and oncoprotein expression. The results show that in situ hybridization of fine-needle aspiration material is a sensitive method to detect increased expression of the ERBB2 and MYC oncogenes in breast carcinoma. Furthermore, this study indicates that in a majority of cases some other mechanism that gene amplification appears responsible for the increased gene expression. It is also possible that Southern blot analysis is not a sensitive enough method to detect gene amplifications in the heterogeneous breast tumors, which usually also contain stromal tissue. The fact that not all cases with elevated ERBB2 mRNA synthesis were immunohistochemically positive suggests that either immunohistochemistry (after fixation with 10% formalin) is a less sensitive method than in situ hybridization to detect abnormal gene expression or that there are cases in which the oncoprotein synthesis is for some reason depressed, even though there is an increase in gene transcription.

Adult↗
PubMed1993

Refinement of regional loss of heterozygosity for chromosome 11p15.5 in human breast tumors.

The familial association of breast cancer with other tumors such as rhabdomyosarcoma that show loss of heterozygosity (LOH) for chromosome 11p15 as well as limited analyses showing LOH for chromosome 11p in breast tumors suggests the presence of a pleiotropic tumor suppressor gene in this region. In order to test this idea, we analyzed DNA samples for 50 matched normal and tumor tissues from unselected breast cancer patients for LOH at loci throughout the chromosome 11p15.5 region. We found that 12.5% of informative cases showed LOH at HRAS1, 26.8% at TH, and 33.3% at both D11S860 and HBB, providing genetic support for this hypothesis. In contrast to previous observations which excluded the involvement of 11p15.5 regions distal to the HBB cluster, our results indicate that the subregion between TH and HBB is a critical region in breast cancer. This region is identical to that identified for the clinically associated tumor, rhabdomyosarcoma, and thus warrants intensive molecular analysis.

Base Sequence↗
PubMed1990

The gene for 17 beta-hydroxysteroid dehydrogenase maps to human chromosome 17, bands q12-q21, and shows an RFLP with ScaI.

The gene encoding human 17 beta-hydroxysteroid dehydrogenase (17-HSD; EC 1.1.1.62) is assigned to chromosome 17 by Southern blotting analyses of panels of human x rodent somatic cell hybrids and independently to 17q12-q21 using chromosomal in situ hybridization. A search for physical linkage between 17-HSD and the proto-oncogenes. THRA1 and ERBB2 (both reported to be located in this region of chromosome 17) was performed by pulsed-field gel electrophoresis (PFGE) using several rare-cutting restriction endonucleases. Because all three genes hybridized to DNA fragments of different lengths it seems unlikely that the gene for 17-HSD is located very close to THRA1 and ERBB2. Further evidence for this assumption was obtained from the absence of any coamplification of the 17-HSD gene in 9 breast tumors with amplification of the ERBB2 gene. Analyses of Southern blots of ScaI-digested DNAs from unrelated individuals from Northern Finland revealed a relatively infrequent diallelic restriction fragment length polymorphism, the allele frequencies of which were 0.04 (A1) and 0.96 (A2).

17-Hydroxysteroid Dehydrogenases↗
PubMedDate not supplied

Alzheimer pathology of patients carrying apolipoprotein E epsilon 4 allele.

A recent report suggested that brains of Alzheimer patients homozygous for APOE epsilon 4 show increased amyloid pathology compared to APOE epsilon 3 homozygotes. We studied APOE allele frequencies in 73 AD patients and 38 controls. We also investigated relation of APOE genotypes to beta/A4 immunopositive plaques, cerebrovascular beta/A4 deposition, neurons expressing paired helical filaments (PHFs), and synaptophysin-like immunopositivity in 22 neuropathologically verified AD patients. We also correlated APOE genotypes of definite AD patients to beta/A4 immunoreactivity in dermal vessel walls detected in lifetime skin biopsy samples. APOE allele epsilon 4 frequency was increased in AD compared to nondemented controls (0.37 vs. 0.11; p = 0.006). The number of beta/A4 immunoreactive plaques, PHFs-containing neurons, the degree of cerebrovascular beta/A4 deposition or synaptophysin-like immunoreactivity did not differ significantly in AD patients with or without epsilon 4. beta/A4 deposition in dermal vessel walls was more frequent in definite AD patients with epsilon 4 (43%) than in patients without epsilon 4 (22%). However, the difference did not reach the statistical significance.

Aged↗
PubMedDate not supplied

Spectral analysis of EEG in Alzheimer's disease: relation to apolipoprotein E polymorphism.

Apolipoprotein E (ApoE) epsilon 4 allele is a risk factor for late-onset Alzheimer's disease (AD) and proposed to have a direct impact on cholinergic function in AD. Slowing of the EEG is characteristic in AD and the cholinergic system has an important role in modulating EEG. Fifty-eight AD patients at the early stage of the disease and 34 age- and sex-matched controls were studied using the quantitative EEG recorded from T6-O2 derivation. AD patients were divided into two subgroups: a) according to the ApoE allele (2 epsilon, 1 epsilon 4, and 0 epsilon 4) and b) according to familial aggregation. AD subgroups did not differ in clinical severity or duration of dementia. The AD patients with the epsilon 4 allele had higher relative theta amplitude and lower relative beta amplitude than controls and patients without the epsilon 4 allele. The peak frequencies were lower in all AD subgroups compared to controls. In conclusion, we found a tendency towards more pronounced EEG slowing in AD patients carrying the epsilon 4 allele. The minor differences in EEG may suggest differences in the degree of the cholinergic deficit in these subgroups.

Aged↗