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Biomedical subjects

M Haltia

Publications and source records attributed to M Haltia.

At least 19 recordsLinked to original sources
PubMed1995

Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein.

BACKGROUND: The epsilon 4 allele of apolipoprotein E has been associated with an increased risk of late-onset Alzheimer's disease. In a cohort of elderly subjects we prospectively investigated the relation between the apolipoprotein E genotype, dementia, and the accumulation of beta-amyloid protein in the cerebral cortex. METHODS: Autopsy involving neuropathological analysis and DNA analysis of frozen blood samples were performed in 92 of 271 persons who were at least 85 years of age, who had been living in Vantaa, Finland, on April 1, 1991, and who had died between that time and the end of 1993. All subjects had been tested for dementia. Apolipoprotein E genotyping was done with a solid-phase minisequencing technique. The percentage of the cortex occupied by methenamine silver-stained plaques was used as an estimate of the extent of beta-amyloid protein deposition. RESULTS: The frequency of the epsilon 4 allele was significantly higher in the subjects with Alzheimer's disease than in the subjects without dementia (30 percent vs. 8 percent, P < 0.001). There was a greater accumulation of beta-amyloid protein in the brain and more neurofibrillary tangles in the subjects with the epsilon 4 allele than in those without it (P < 0.001). The deposition of beta-amyloid protein varied according to the genotype in both the subjects with dementia and those without dementia: it was lowest in those with the epsilon 2/epsilon 3 genotype, intermediate in those with the epsilon 3/epsilon 3 genotype, and highest in those with the epsilon 3/epsilon 4 genotype. A single subject had the epsilon 4/epsilon 4 genotype and had dementia. CONCLUSIONS: The epsilon 4 allele of apolipoprotein E is significantly associated with Alzheimer's disease. Even in elderly subjects without dementia, the apolipoprotein E genotype is related to the degree of deposition of beta-amyloid protein in the cerebral cortex.

Aged↗
PubMed1995

Sphingolipid activator proteins (SAPs) are stored together with glycosphingolipids in the infantile neuronal ceroid-lipofuscinosis (INCL).

The storage material isolated from the brains of patients with infantile neuronal ceroid-lipofuscinosis (INCL) contains, on average, 43% protein and 35% lipids on a dry weight basis. Recently we identified the major storage proteins as sphingolipid activator proteins (SAPs) A and D by direct sequencing. In the present study we used monospecific anti-sap-B-, anti-sap-C, and anti-sap-D-antisera in immunohistochemical and Western analyses to show that sap-D is, indeed, an integral component of the storage bodies. In contrast, no (or little) immunoreactivity for sap-B or sap-C was detected in the INCL storage granules. This observation is of interest for an understanding of the pathogenesis because the four SAPs are produced from a single precursor protein by proteolytic cleavage. Furthermore, we analysed the stored lipids on high performance thin layer chromatography combined with different staining techniques. In this preliminary analysis we found two glycosphingolipids, yet to be identified, to be common for all INCL patients.

Adolescent↗
PubMed1995

Sphingolipid activator proteins in the neuronal ceroid-lipofuscinoses: an immunological study.

The molecular defects underlying neuronal ceroid-lipofuscinoses (NCL) are still unknown. However, more data exist on the composition of the hydrophobic storage material characteristic of NCL. Accumulation of subunit c of the mitochondrial ATP synthase has been shown in most forms of human NCL with the exception of the infantile NCL (INCL) for which we have recently demonstrated storage of sphingolipid activator proteins (SAP). In the present study we raised an antiserum against storage cytosomes purified from INCL brain. Using the anti-INCL antiserum and monospecific SAP antisera, we studied storage material isolated from the brains of patients affected with NCL by Western analysis, and found a 12-kDa protein showing a SAP-like immunoreactivity not only in INCL, but also in all the childhood forms of NCL. Furthermore, using the anti-sap-D antiserum for immunohistochemistry, we observed strong immunoreactivity of the storage cytosomes in all major forms of NCL, and also in tissues of non-neuroectodermal origin. From these data we conclude that the presence of SAP within the storage bodies is a phenomenon common to all major forms of human NCL.

Adolescent↗
PubMed1995

An autosomal locus predisposing to deletions of mitochondrial DNA.

The molecular mechanisms by which the nuclear genome regulates the biosynthesis of mitochondrial DNA (mtDNA) are only beginning to be unravelled. A naturally occurring in vivo model for a defect in this cross-talk of two physically separate genomes is a human disease, an autosomal dominant progressive external ophthalmoplegia, in which multiple deletions of mtDNA accumulate in the patients' tissues. The assignment of this disease locus to 10q 23.3-24.3 is the first direct evidence for involvement of both nuclear and mitochondrial genomes in a single disorder.

Base Sequence↗
PubMed1995

Proliferative activity and DNA index do not significantly predict survival in primary central nervous system lymphoma.

Proliferative activity and DNA index were analyzed and correlated with histology and survival in 30 primary central nervous system lymphomas (PCNSL) in immunocompetent patients. Proliferative activity was determined using mitotic activity index and volume-corrected mitotic index, percentage of Ki-67 (MIB-1) immunopositive nuclei and flow cytometric S-phase fraction. Twenty-nine PCNSL were of B-cell origin and one of T-cell; by Kiel classification there were 23% low grade and 77% high grade and by Working Formulation there were 7%, 73% and 20% low, intermediate and high grade tumors, respectively. Mean survival time for non-survivors (n = 26) was 11.5 months and median 6.5 months. When indicators of proliferative activity were evaluated against histological grading, correlation existed only between mitotic activity index and Kiel classification. None of the proliferation markers or DNA index correlated significantly with survival, but there was a trend for patients with higher volume-corrected mitotic index to have shorter survival. In conclusion, most PCNSL have poor prognosis irrespective of their histological grade and proliferative activity. Furthermore, because at present stereotactic biopsy is recommended for establishing the diagnosis, exact histological subtyping and determination of proliferation activity in such small samples appears to be of only marginal significance.

Adult↗
PubMed1995

Expression of endothelial cell-specific receptor tyrosine kinases and growth factors in human brain tumors.

Key growth factor-receptor interactions involved in angiogenesis are possible targets for therapy of CNS tumors. Vascular endothelial growth factor (VEGF) is a highly specific endothelial cell mitogen that has been shown to stimulate angiogenesis, a requirement for solid tumor growth. The expression of VEGF, the closely related placental growth factor (PIGF), the newly cloned endothelial high affinity VEGF receptors KDR and FLT1, and the endothelial orphan receptors FLT4 and Tie were analyzed by in situ hybridization in normal human brain tissue and in the following CNS tumors: gliomas, grades II, III, IV; meningiomas, grades I and II; and melanoma metastases to the cerebrum. VEGF mRNA was up-regulated in the majority of low grade tumors studied and was highly expressed in cells of malignant gliomas. Significantly elevated levels of Tie, KDR, and FLT1 mRNAs, but not FLT4 mRNA, were observed in malignant tumor endothelia, as well as in endothelia of tissues directly adjacent to the tumor margin. In comparison, there was little or no receptor expression in normal brain vasculature. Our results are consistent with the hypothesis that these endothelial receptors are induced during tumor progression and may play a role in tumor angiogenesis.

Adult↗
PubMed1994

Chromosome 14-encoded Alzheimer's disease: genetic and clinicopathological description.

A family of Finnish descent with very-early-onset Alzheimer's disease has been identified. Genetic analysis of this family eliminated the amyloid precursor protein gene as the pathogenic locus, but strongly implicated a locus on chromosome 14q23.4 between D14S52 and D14S55. The early age at onset of the disease (average, 36 years; range, 35-39 years), the rapid progression, and the early and prominent myoclonus, while they appear to be frequent findings in the chromosome 14-encoded form of Alzheimer's disease, raised the clinical suspicion of prion disease. However, sequencing the prion gene-coding region of 2 affected members of the pedigree failed to show any abnormality. Apart from the presence of modest cortical vacuolar change, the pathological features of our index patient appeared typical of Alzheimer's disease with abundant senile plaques immunoreactive with beta-amyloid, but not with prion protein antibodies.

Adult↗
PubMed1994

Autonomic nervous system and cardiac involvement in familial amyloidosis, Finnish type (FAF).

Familial amyloidosis, Finnish type (FAF), is a gelsolin-related inherited systemic amyloidosis. We report autonomic nervous system and cardiac findings in a study of 30 FAF patients (18 females, 12 males aged 27-74 years; mean 53.9 years). Cardiovascular reflex tests showed a significant decrease in heart rate variation in FAF patients compared with healthy controls. Orthostatic hypotension was found in 9 of 28 FAF patients, but only in 3 of 69 controls. Signs of amyloid cardiopathy were rare at clinical examination and in radio-, echocardio- and electrocardiographic examinations. Histological and immunohistochemical studies revealed amyloid deposition and immunoreactivity against the gelsolin-related FAF amyloid subunit in autonomic nervous system structures and in cardiac tissue in 3 autopsied FAF patients. The results show that minor autonomic nervous system dysfunction can be found in FAF, while clinically significant amyloid cardiopathy or autonomic neuropathy is not characteristic of this type of amyloidosis.

Adult↗
PubMed1994

Toward understanding the pathogenic mechanisms in gelsolin-related amyloidosis: in vitro expression reveals an abnormal gelsolin fragment.

Gelsolin-related amyloidosis, also called familial amyloidosis, Finnish type (FAF) is an autosomal dominantly inherited disorder characterized by progressive polyneuropathy and corneal lattice dystrophy. All the analyzed patients are found to carry a nucleotide substitution of A or T for G654 in their gelsolin gene, which at the protein level results in the conversion of the 187 amino acid residue, aspartic acid, to asparagine or tyrosine, respectively. In this study, we transfected mammalian mesenchymal COS-1 cells with a derivative of the expression vector pCD-X containing cDNA coding for the wild-type (D187) and mutant forms (N187 and Y187) of plasma gelsolin. Both disease-associated mutant forms of gelsolin were found to be abnormally processed, which led to the secretion of an aberrant 68 kDa gelsolin fragment into the culture media. This fragment most probably represents a carboxy-terminal part of the protein and contains the suggested amyloid-forming sequence. Initial data were also obtained for involvement of a metalloendoprotease in the pathologic processing. This aberrant proteolysis is likely to represent a crucial initiator step in the cascade resulting in amyloid accumulation in patients' tissues.

Amyloid Neuropathies↗
PubMed1994

Ocular amyloid deposition in familial amyloidosis, Finnish: an analysis of native and variant gelsolin in Meretoja's syndrome.

PURPOSE: To analyze the deposition of amyloid and its precursors in eyes of patients with familial amyloidosis, Finnish (FAF; Meretoja's syndrome), a hereditary systemic amyloidosis. METHODS: Autopsy eyes from three patients with FAF and ten control eyes were studied by Congo red staining and with antibodies to the nonmutated part of gelsolin (GS-2C4), the mutated gelsolin Asn-187 fragment (AGel), and amyloid-P component (AP). RESULTS: Congo red and antisera to AP and AGel bound to amyloid deposits in the cornea and conjunctiva, the sclera, the perineurium of ciliary nerves, the walls of ciliary vessels, the optic nerve sheaths, the stroma of the ciliary body, and along the choriocapillaris. mAb GS-2C4 bound weakly and focally to most deposits and strongly around the choriocapillaris. It labeled the corneal epithelium and endothelium, keratocytes, scleral fibroblasts, trabecular and lens epithelial cells, the ciliary muscle and epithelium, the iris sphincter and dilator, and stromal cells of the conjunctiva and uveal tract. CONCLUSIONS: Local production, especially in the cornea, conjunctiva, sclera, and ciliary muscle, and systemic deposition, particularly in blood vessles and in the sclera, may contribute to amyloid deposits in FAF. To explain the complex pattern of deposition, microenvironmental factors such as lamellar architecture of the cornea and sclera, altered processing of gelsolin, or blood-tissue barriers must be invoked. In addition to corneal lattice dystrophy type II, the observed deposits help to explain glaucoma in patients with FAF.

Aged↗
PubMed1993

Immunohistochemical analysis of lattice corneal dystrophies types I and II.

Corneal buttons from four patients with lattice corneal dystrophy (LD) type I, thought to be an isolated corneal amyloidosis, and from six patients with LD type II, part of systemic familial amyloidosis, Finnish type (FAF; Meretoja's syndrome), were studied by immunohistochemistry to determine the differential distribution in the amyloid deposits of amyloid P component (AP), mutated gelsolin specific for FAF, and native gelsolin. In both types of LD, antibodies to AP labelled lattice lines and a discontinuous layer of amyloid deposits under Bowman's layer. In LD type II, particularly, they also reacted with streak-like amyloid deposits between corneal almellae, especially in the limbal region. While the anti-FAF antiserum strongly labelled all amyloid deposits in LD type II, it failed to react unequivocally with them in LD type I. Both in LD type I and in two control specimens representing granular dystrophy, the monoclonal antibody (MAb) GS-2C4 to gelsolin faintly labelled some deposits, while in LD type II it reacted non-homogeneously with most amyloid deposits. In all specimens, MAb GS-2C4 labelled corneal epithelial cells and occasional stromal keratocytes and endothelial cells. The results suggest that Meretoja's syndrome, a systemic disease, can be diagnosed even retrospectively from corneal buttons subjected to histopathological study.

Adult↗
PubMed1992

Linkage map of the chromosomal region surrounding the infantile neuronal ceroid lipofuscinosis on 1p.

The neuronal ceroid lipofuscinoses (NCLs) of childhood are divided into 3 main types according to age-of-onset, clinical course, and neurophysiological and neuropathological findings: infantile, late infantile, and juvenile. All forms are inherited as an autosomal recessive trait, and their biochemical background is still unknown. The infantile type (INCL) with the earliest age-of-onset and the most severe clinical course, occurs in Finland with an incidence of 1:20,000, i.e., 116 patients have been found in our country up to now, whereas only about 50 cases have been reported from other parts of the world. Earlier we reported the linkage of INCL to the short arm of chromosome 1. Here we describe a more precise linkage map of this area. Our current map places the INCL mutation between D1S57 and D1S79; D1S7 has so far shown no recombination events between the marker and the disease (lod score 4.55 at theta = 0.00). Our material includes 64% of all living patients in Finland, and no linkage disequilibrium of haplotypes is seen, using the 2 physically close markers D1S57 and D1S79. This finding as well as our LINKMAP analyses suggest that the distance between the disease locus and the flanking markers is about 3-4 cm.

Chromosome Mapping↗
PubMed1992

Mitochondrial ATP synthase subunit c storage in the ceroid-lipofuscinoses (Batten disease).

The ceroid-lipofuscinoses (Batten disease) are neurodegenerative inherited lysosomal storage diseases of children and animals. A common finding is the occurrence of fluorescent storage bodies (lipopigment) in cells. These have been isolated from tissues of affected sheep. Direct protein sequencing established that the major component is identical to the dicyclohexylcarbodiimide (DCCD) reactive proteolipid, subunit c, of mitochondrial ATP synthase and that this protein accounts for at least 50% of the storage body mass. No other mitochondrial components are stored. Direct sequencing of storage bodies isolated from tissues of children with juvenile and late infantile ceroid-lipofuscinosis established that they also contain large amounts of complete and normal subunit c. It is also stored in the disease in cattle and dogs but is not present in storage bodies from the human infantile form. Subunit c is normally found as part of the mitochondrial ATP synthase complex and accounts for 2-4% of the inner mitochondrial membrane protein. Mitochondria from affected sheep contain normal amounts of this protein. The P1 and P2 genes that code for it are normal as are mRNA levels. Oxidative phosphorylation is also normal. These findings suggest that ovine ceroid-lipofuscinosis is caused by a specific failure in the degradation of subunit c after its normal inclusion into mitochondria, and its consequent abnormal accumulation in lysosomes. This implies a unique pathway for subunit c degradation. It is probable that the human late infantile and juvenile diseases and the disease in cattle and dogs involve lesions in the same pathway.

Amino Acid Sequence↗
PubMed1992

Stored dolichyl pyrophosphoryl oligosaccharides in Batten disease.

Each of the 3 childhood forms of Batten disease, juvenile (JB), late-infantile (LIB), and infantile (IB), have abnormally high brain concentrations of dolichyl pyrophosphoryl oligosaccharides (Dol-PP-OS). In this study, the carbohydrate portions of Dol-PP-OS were analysed: in JB and LIB, they range in size from Man2GlcNAc2 to Glc3Man9GlcNAc2, predominant components being Man5-7GlcNAc2 and Glc3Man7GlcNAc2. In IB, they range from Man6-9GlcNAc2, no glucose containing oligosaccharides being identified. In Batten disease, the main subcellular location of Dol-PP-OS is within storage material, where it represents up to 7% of the dry weight. [3H]-Mannose incorporation experiments with cultured fibroblasts show that synthesis of Dol-PP-OS in JB is normal. We infer that the glycosylation intermediate Glc3Man9GlcNAc2-PP-dolichol is synthesised normally within the endoplasmic reticulum in Batten disease, but that catabolic derivatives accumulate within the lysosomes. It is unclear whether this process is central to the pathogenesis of the disease, though in IB a defect in the release of mannose residues from Dol-PP-OS is a distinct possibility.

Carbohydrate Sequence↗
PubMed1992

Gelsolin gene mutation--at codon 187--in familial amyloidosis, Finnish: DNA-diagnostic assay.

Familial amyloidosis, Finnish (FAF), is an autosomal dominant form of systemic amyloidosis with lattice corneal dystrophy and progressive cranial neuropathy as principal clinical manifestations. We have shown that the novel amyloid fibril protein found in these patients is an internal degradation fragment of gelsolin, an actin-binding protein, and that it contains an amino acid substitution, asparagine for aspartic acid at position 15, that is due to a guanine-to-adenine transversion corresponding to codon 187 of human plasma gelsolin cDNA. To test that this mutation cosegregates with the disease high-molecular-weight genomic DNA was isolated from autopsied tissues or lymphocytes of 23 patients, 6 healthy relatives and 20 unrelated healthy control persons. Specific fragments were amplified with the polymerase chain reaction for oligonucleotide hybridization analysis using the slot-blot technique. The guanine-to-adenine transversion was found in all FAF patients tested, but in none of the control subjects. Our results show that the mutation (G to A) cosegregates with the disease phenotype, and that the slot-blot analysis can be used as a diagnostic assay, including prenatal evaluation.

Amyloidosis↗
PubMed1992

Creutzfeldt-Jakob disease cosegregates with the codon 178Asn PRNP mutation in families of European origin.

We recently discovered an amino acid-altering heterozygous mutation in codon 178 of the PRNP amyloid precursor gene in patients with familial Creutzfeldt-Jakob disease. This mutation is now shown to be associated with the occurrence of disease in 7 unrelated families of Western European origin, among which a total of 65 members are known to have died from Creutzfeldt-Jakob disease. The mutation was detected in each of 17 tested patients, including at least 1 affected member of each family, and in 16 of 36 of their first-degree relatives, but not in affected families with other mutations, patients with the nonfamilial form of the disease, or 83 healthy control individuals. Linkage analysis in two informative families yielded a lod score of 5.30, which, because no recombinants were found, strongly suggests that codon 178Asn is the actual disease mutation.

Adult↗
PubMed1992

Phenotypic characteristics of familial Creutzfeldt-Jakob disease associated with the codon 178Asn PRNP mutation.

A group of 43 patients from seven families affected by Creutzfeldt-Jakob disease (CJD) with the codon 178Asn mutation of the PRNP amyloid precursor gene is compared to a group of 211 patients with the sporadic form of the disease. As a group, the patients with the codon 178Asn mutation had an earlier age at onset of illness (almost always presenting as an insidious loss of memory), a longer duration of illness, and an absence of periodic electroencephalographic activity. Transmission of disease to primates was accomplished using brain tissue homogenates from 6 of 10 patients, resulting in significantly shorter incubation periods than those due to sporadic CJD inocula. These findings are interpreted and discussed in terms of possible differences in the temporospatial evolution of damage to the brain, and of accelerated induction of polymerized amyloid protein by its mutationally altered template precursor.

Age Factors↗