Biomedical subjects
M Haltia
Publications and source records attributed to M Haltia.
[New variant of Alzheimer's disease].
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Muscle-eye-brain disease: a neuropathological study.
A combination of congenital central nervous, ocular and muscular abnormalities is characteristic of muscle-eye-brain disease (MEB), of Fukuyama congenital muscular dystrophy (FCMD), and of Walker-Warburg syndrome (WWS). The nosological relationship of these inherited malformative disorders is still unestablished, although the genetic locus for FCMD has been excluded in MEB. We present the first postmortem neuropathological study of MEB based on 2 male patients. Apart from sharply limited occipital agyric areas, their brains showed coarse gyri with an abnormally nodular surface ("cobblestone cortex"). Both the cerebral and cerebellar cortices showed a total disorganization without horizontal lamination. The haphazardly oriented cortical neurons formed irregular clusters or islands, separated by gliovascular strands extending from the pia. The ocular abnormalities included a pronounced glial preretinal membrane. Although MEB shares the cobblestone cortex-type malformation with FCMD and WWS, the cerebral and ocular manifestations are less severe than in WWS. Furthermore, a consistently weak staining for laminin alpha2 chain (merosin) was found in muscle biopsy specimens from 4 MEB patients, while normal immunoreactivity was observed for the laminin beta2 chain, reported to be severely deficient in WWS. These findings support nosological independence of MEB.
MRI of neuronal ceroid lipofuscinosis. II. Postmortem MRI and histopathological study of the brain in 16 cases of neuronal ceroid lipofuscinosis of juvenile or late infantile type.
Postmortem MRI was carried out on the formalin-fixed brains of 14 patients with juvenile (JNCL) and two with late infantile neuronal ceroid lipofuscinosis, one of variant and the other of classical type. Two patients with JNCL had also undergone MRI during life. After MRI, specimens for histopathological analysis were taken from standard areas of the cerebral cortex, deep nuclei and white matter. The signal intensity of the periventricular white matter was usually higher than that of the peripheral white matter, a finding which correlated with the severe periventricular loss of myelin and gliosis observed histologically. The signal intensity was usually lower in the thalamus than in the putamen; in some patients the signal intensity of the thalamus was equal to or even lower than that of the white matter. However, myelin loss, gliosis, the storage process or neuronal loss in the thalamus did not correlate with the MRI findings. Since in one patient with JNCL the ante- and postmortem MRI did not differ basically, it appears probable that the periventricular changes detected in vivo on MRI are due to the severe loss of myelin and gliosis observed in this study. However, changes resulting from the fixation process must be considered, when postmortem and in vivo MRI are correlated.
Sphingolipid activator proteins (SAPs) in neuronal ceroid lipofuscinoses (NCL).
Based on the predominant component of the storage material the neuronal ceroid lipofuscinoses (NCL) can be divided into two categories: one storing mitochondrial ATP synthase subunit c and the other storing sphingolipid activator proteins (SAPs). The latter group is represented by the human infantile NCL (INCL), a congenital ovine NCL, and a canine NCL. Small amounts of SAPs also accumulate in most other forms of NCL. The SAPs, their functions and occurrence in different forms of NCL, as well as the relationship between SAPs and palmitoyl protein thioesterase, an enzyme implicated in INCL, are discussed.
Variant late infantile neuronal ceroid-lipofuscinosis: pathology and biochemistry.
The neuronal ceroid-lipofuscinoses (NCL) are among the most common inherited neurodegenerative disorders of childhood. The genomic defect causing a variant late infantile neuronal ceroid-lipofuscinosis (vLINCL, also called CLN-5 or variant Jansky-Bielschowsky disease) has recently been localized to chromosome 13q22, thus delineating this disease as a separate entity. This particular form of NCL is clinically well defined, but lacks pathomorphological and biochemical description. The present analyses indicate that subunit c of the mitochondrial ATP synthase is the major protein in vLINCL brain storage cytosomes. These cytosomes also contain minor amounts of sphingolipid activator proteins (SAPs). The immunohistological distribution of subunit c and SAPs in the central nervous system (CNS) and visceral tissues closely resembles that of classical LINCL. Thus, despite clinical differences and the fact that various forms of NCL are caused by different genetic defects, variant and classical LINCL as well as juvenile NCL are all characterized by pronounced lysosomal accumulation of the same hydrophobic protein, subunit c of the mitochondrial ATP synthase.
Aspartylglucosaminuria: radiologic course of the disease with histopathologic correlation.
Twelve living patients (aged 19 months to 32 years) with aspartylglucosaminuria were examined by magnetic resonance imaging (MRI), and the magnetic resonance (MR) images of 16 health volunteers (aged 4 to 32 years) were used as controls. One patient was examined twice. Postmortem MRI and histopathologic analysis were done on the brains of four additional adult patients. Signal intensities determined quantitatively on T2-weighted images differed significantly between patients and controls, being higher from the white matter (P < .0002) and lower from the thalami (P < .03) in the patients. The generally increased signal intensity of the white matter was most obvious in the young patients, with many focal areas of very high signal intensity in the subcortical white matter. The subcortical white matter showed a somewhat increased signal intensity even at the age of 32 years. In two of the four postmortem MR images, the distinction between the gray and white matter was still poor. At histopathologic analysis, the basic cortical cytoarchitecture was generally preserved but most neurons contained vacuoles, which were also found in the neurons of the deep gray matter. In two of the four autopsy cases the white matter showed diffuse pallor of myelin staining and some gliosis. Thus aspartylglucosaminuria is primarily a gray-matter disease also affecting white matter by delaying myelination.
Autosomal dominant progressive external ophthalmoplegia with multiple deletions of mtDNA: clinical, biochemical, and molecular genetic features of the 10q-linked disease.
Autosomal dominant progressive external ophthalmoplegia (adPEO) is a mitochondrial disease characterized by accumulation of multiple large deletions of mtDNA in patients' tissues. We previously showed that the disease is genetically heterogeneous by assigning two nuclear loci predisposing to mtDNA deletions: one on chromosome 10q 23.3-24.3 in a Finnish family and one on 3p 14.1-21.2 in three Italian families. To reveal any locus-specific disease features, we report here the clinical, biochemical, and molecular genetic characteristics of the 10q-linked disease in the single family reported to date. All seven patients and four asymptomatic subjects had ragged-red fibers and multiple deletions of mtDNA in their muscle. Ptosis and external ophthalmoplegia were the major clinical findings, and depression or avoidant personality traits were frequently, but not consistently, present in the subjects carrying mutant mtDNA. In six of the subjects with mutant mtDNA, the activities of the respiratory chain complexes I or IV, or both, were below or within the low normal range. Two autopsy studies revealed the characteristic distribution of mutant mtDNA in these patients: highest proportion of mutant mtDNA is found in different parts of the brain, followed by the skeletal and ocular muscle, and the heart.
Proliferation potential and histological features in neurofibromatosis 2-associated and sporadic meningiomas.
The authors compared the histological appearance and proliferation potential of 35 meningiomas in patients with neurofibromatosis 2 (NF2) and 30 sporadic meningiomas in age- and gender-matched patients without NF2. The NF2 meningiomas showed more mitotic figures (p < 0.001) and nuclear pleomorphism (p = 0.003) than the sporadic meningiomas; however, the incidence of meningothelial, fibroblastic, and transitional subtypes occurred equally in both groups. The proliferation potential was significantly higher in the 35 meningiomas removed from 23 patients with NF2 than in the 30 sporadic meningiomas removed in the 30 patients without NF2 (mean MIB-1 labeling indices: 2.5 vs. 1.75, p = 0.0147). The higher proliferation potential of the NF2 meningiomas may reflect differences in molecular biology between sporadic and NF2 meningiomas and may be related to an earlier onset, multiplicity, and more aggressive behavior of NF2 tumors.
[Apoptosis during development of the nervous system and in degenerative diseases].
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[New variant of Creutzfeldt-Jakob disease].
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[The Nobel prize in medicine for a prion researcher].
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Diffuse vacuolization (spongiosis) and arteriolosclerosis in the frontal white matter occurs in vascular dementia.
OBJECTIVE: To examine quantitatively white-matter changes at different sites in patients with definite vascular dementia and Alzheimer's disease. DESIGN: Prospective clinical and neuropathological series. SETTING: University Hospital clinics (Helsinki, Finland and London, Ontario). SUBJECTS: Twenty-two patients with a clinical and neuropathological diagnosis of vascular dementia and 20 patients with Alzheimer's disease. MEASURES: The frequencies of focal white-matter lesions, arteriolosclerosis, and cerebral amyloid angiopathy were assessed. Validated ratings and cell counts were done in the subcortical U-fiber, centrum semiovale, and periventricular areas of the frontal white matter. Degrees of abnormality (none, mild, moderate, severe) were rated for spongiosis (vacuolization of white matter), état criblé (widening of perivascular spaces), myelin loss, oligodendrocyte density, axonal loss, and overall. Densities of oligodendrocytes and astrocytes (cells per square millimeter) were determined. RESULTS: Patients with vascular dementia showed focal white-matter lesions and arteriolosclerosis more often than patients with Alzheimer's disease. The patients with vascular dementia also had significantly greater spongiosis (P<.001), état criblé (P=.004), myelin loss (P<.005) and overall white-matter abnormality (P<.001). Arteriolosclerosis was found in association with spongiosis but not with état criblé. Cerebral amyloid angiopathy did not appear to be related to any of the white-matter changes in patients with either vascular dementia or Alzheimer's disease. The U-fiber area showed fewer changes, and the periventricular area tended to be most affected. CONCLUSION: In addition to focal infarcts, patients with vascular dementia showed widespread diffuse changes, including spongiosis and arteriolosclerosis, along with état criblé and myelin loss. White-matter changes in patients with Alzheimer's disease could not be related to infarction. Pathologic changes in small blood vessels are associated with diffuse white-matter changes and may have a distinct role in the genesis of vascular dementia.
Amyloid beta protein (Abeta) deposition in chromosome 14-linked Alzheimer's disease: predominance of Abeta42(43).
Amyloid beta protein (Abeta) deposition was investigated in the frontal cortex of 8 cases of (genetically confirmed) chromosome 14-linked Alzheimer's disease (AD) using the end-specific monoclonal antibodies BA27 and BC05 to detect the presence of Abeta40 and Abeta42(43), respectively. In all patients, Abeta42(43) was the predominant peptide species present. The total amount of Abeta40 and Abeta42(43) deposited was more than twice the amount deposited in cases of sporadic AD of similar disease duration, although the ratio between the extent of Abeta40 and Abeta42(43) deposition was unaltered, compared with sporadic AD. Therefore, (one of) the effects of the mutations in the presenilin 1:PS-1 (S182) gene may be to cause or at least promote an early and excessive deposition of Abeta42(43) within the brain, a property shared with other inherited forms of AD, such as those due to amyloid precursor protein mutations, and Down's syndrome (trisomy 21).
Different expression of adhesion molecules on stromal cells and endothelial cells of capillary hemangioblastoma.
Cell-cell and cell-matrix interactions are essential for many basic functions, including differentiation and development. In pathological conditions such as inflammation and tumorigenesis adhesive events also play a major role. Cellular adhesion is mediated by specific molecules expressed by both normal and neoplastic tissues. Capillary hemangioblastoma is a tumor of controversial origin, characterized by two major components, vacuolated stromal cells and a capillary network. In order to shed light on the differentiation of the stromal cells and the interactions between the two major components of hemangioblastoma we studied the expression of several adhesion molecules by immunocytochemistry. The endothelium-associated adhesion molecules (ICAM-1, ICAM-2, VCAM-1, PECAM-1 and ELAM-1) were expressed by endothelial cells within the tumors, but not by stromal cells. In contrast, the stromal cells showed strong neuronal cell adhesion molecule (NCAM/CD56) expression, further distinguishing them from endothelial cells. In addition, the stromal cells expressed CD44, which is of interest, as this membrane protein is linked to ezrin, a cytoskeleton-associated protein also expressed by stromal cells. We conclude that the stromal cells and endothelial cells of capillary hemangioblastoma exhibit quite divergent expression patterns of adhesion molecules. The NCAM expression in stromal cells suggests neuroectodermal or mesenchymal differentiation of this tumor. In addition, the NCAM expression could contribute to the sometimes problematic differential diagnosis between capillary hemangioblastoma and metastatic renal cell carcinoma of the central nervous system.
Expression of growth factors and growth factor receptors in capillary hemangioblastoma.
To elucidate the mechanisms underlying the regulation of growth and differentiation of capillary hemangioblastoma we studied the expression of selected growth factors and growth factor receptors by immunocytochemistry. As stromal cells of capillary hemangioblastoma express high levels of vascular endothelial growth factor (VEGF) and placental growth factor (P1GF) mRNA, we studied the distribution of the corresponding VEGF and P1GF proteins. We also studied the expression of epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptors (PDGFR) because their ligands have been reported to promote angiogenesis. The stromal cells expressed abundant EGFR and, in addition, some stromal cells expressed PDGFR-alpha but not PDGFR-beta. In contrast, the endothelial cells co-expressed PDGFR-alpha and PDGFR-beta. VEGF and P1GF were expressed by scattered stromal cells; however, more intense staining was observed in the endothelial cells of the intratumoral blood vessels, possibly indicating the secreted growth factors bound to their target receptors. We conclude that capillary hemangioblastomas express a variety of growth factor receptors and ligands, potentially involved in both autocrine and paracrine loops. The uniformly high EGFR expression is unique among brain tumors and may be associated with the typical morphology of capillary hemangioblastoma. The expression of highly angiogenic growth factors and their receptors may contribute to the rich vascularity of this enigmatic tumor.
Tie endothelial cell-specific receptor tyrosine kinase is upregulated in the vasculature of arteriovenous malformations.
Arteriovenous malformations (AVMs) are congenital lesions composed of abnormal vasculature, with no capillary component, and are clinically significant due to their tendency to spontaneously hemorrhage. The mechanisms regulating the genesis and progression of these lesions are unknown. In order to study the role of angiogenesis in AVMs, we have analyzed the expression of the endothelial cell mitogen vascular endothelial growth factor (VEGF) and a novel endothelial cell-specific receptor tyrosine kinase, Tie, by in situ hybridization and immunohistochemistry in these malformations and surrounding brain tissue. We have previously shown upregulation of Tie accompanying wound healing and tumor progression. In this study, we demonstrate significantly elevated levels of Tie mRNA and protein in AVM and surrounding brain vasculature. Upregulation of VEGF mRNA was observed in the cells of brain parenchyma adjacent to the AVM, and VEGF protein was detected in this tissue as well as in AVM endothelia. Normal brain, in comparison, expressed little or no Tie or VEGF. The significant upregulation of VEGF and Tie in AVMs may indicate some ongoing angiogenesis, possibly contributing to the slow growth and maintenance of the AVM, and could be of potential use in the therapeutic targeting of these lesions.
Neuronal ceroid-lipofuscinosis--late-infantile or Jansky-Bielschowsky type--revisited.
The tissues from three patients with late-infantile NCL originally described by Max Bielschowsky became available to apply modern techniques such as fluorescence microscopy, electron microscopy and immunohistochemistry. While regular tinctorial preparations of the tissues documented a neuronal storage disorder in all three patients' tissues, the accumulated material proved to be autofluorescent, showed the ultrastructure of curvilinear lipopigments, and reacted strongly with an antibody against the subunit-C of mitochondrial ATP synthase, a major component of lipopigments in NCL and also with an antibody against sphingolipid activator proteins. Thus, these modern morphological techniques demonstrated that the originally described three siblings with late-infantile "amaurotic familial idiocy" really had neuronal ceroid-lipofuscinosis of the late-infantile or Jansky-Bielschowsky type, according to current diagnostic criteria. This type of archival study may also contribute to the mosaic of medical history.