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Biomedical subjects

H Budka

Publications and source records attributed to H Budka.

At least 19 recordsLinked to original sources
PubMed1999

Early destruction of the extracellular matrix around parvalbumin-immunoreactive interneurons in Creutzfeldt-Jakob disease.

GABA-interneurons immunoreactive (IR) for the calcium-binding protein parvalbumin are lost during the early stages of Creutzfeldt-Jakob disease (CJD) and diminution in their number may partially account for the neurological disturbances manifested in patients suffering from this condition. The disease is characterized by a transformation of the prion protein, PrP(c)-a host-coded sialoglycoprotein-to its protease-resistant and putatively pathological form, PrP(CJD). And since this conversion is likely to take place at the cell surface, we were curious to know whether the "perineuronal net"-a characteristic accumulation of extracellular matrix in intimate contact with the surface of parvalbumin-IR neurons-is implicated in the early disappearance of the mantled cells. Using various lectins and antibodies as markers for the perineuronal net in brains of 21 CJD victims, we observed that this meshwork of extracellular matrix molecules is lost before the embraced parvalbumin-IR neurons themselves disappear. Hence, an interaction of PrP(c) and/or PrP(CJD) with components of the extracellular matrix around this subpopulation of nerve cells precipitates a sequence of as yet unknown events which culminates in the replacement of perineuronal nets by deposits of insoluble PrP(CJD). This change in the environment of the GABA-interneurons IR for parvalbumin may ultimately provoke their death.

Aged↗
PubMed1999

Neuroaxonal pathology in Creutzfeldt-Jakob disease.

Neuroaxonal pathology has met little attention in transmissible spongiform encephalopathies. In brains of a series of 39 consecutive Creutzfeldt-Jakob disease (CJD) cases, we detected numerous abnormal neurites that labeled for neurofilament proteins (NFP) by immunocytochemistry. Three types of abnormally NFP-accumulating structures were more prominently observed in CJD brains than in age-matched control brains: 1. Neurons with NFP in their somata were seen in 29 CJD cases (74%), some appearing distended with eccentrically placed nuclei and homogenously stained cytoplasm. 2. Neuritic distensions (neuritic swellings, dystrophic neurites) were observed mainly in the white matter but also at the junction between gray and white matter. In some axons many such swellings could be traced along the visible part of the axonal segment. 3. Axonal spheroids were observed mainly in the medulla, predominantly but not exclusively in posterior nuclei, and were more numerous than in age-matched control brains. Several neurons, axons and spheroids demonstrated immunoreactivity for amyloid precursor protein. Their number was much smaller, however, than that of NFP-immunoreactive structures and varied from one or two immunopositive neurites per section to small clusters of beaded or spiral axons. Focal expression of apolipoprotein E in cells of microglial and astrocytic morphology was observed in areas with most pronounced axonal damage. We conclude that neuroaxonal pathology is a frequent and important part of brain lesioning in CJD, probably reflecting profound impairment of axonal transport.

Adult↗
PubMed1999

Vascular changes in white matter lesions of Alzheimer's disease.

The pathogenesis of white matter lesions observed in Alzheimer's disease (AD) is not completely clear. We tested the hypothesis that white matter lesions are correlated with medullary artery sclerosis rather than with amyloid angiopathy. A total of 57 brains were examined, including 39 derived from patients with AD and 13 from patients with Binswanger's disease (BD) along with 5 from non-neurological patients. Moderate or severe amyloid deposits in the meningocortical segment were observed in 32 out of 39 AD patients (82.1%), and in 2 out of 13 BD patients (15.4%). These deposits were not observed in the white matter segment, except for 2 patients with AD. The BD patients invariably had marked white matter lesions and fibrohyalinosis in the medullary arteries, with a mean sclerotic ratio of 48.1%. In contrast, the AD patients had mild or moderate white matter lesions and a sclerotic ratio of 37.9%, which was significantly greater than the controls. The scores for white matter lesions were correlated with the sclerotic ratio of the medullary arteries, but not with the ages of onset or the scores for amyloid angiopathy. Although amyloid angiopathy is an independent risk of white matter lesions, its role is limited in the pathogenesis of those associated with AD. Wall thickening of the medullary arteries, likely due to fibrohyalinosis, is closely correlated with the white matter lesions in AD, thus indicating a heterogeneity in its etiology.

Aged↗
PubMed1999

Proliferative activity as measured by MIB-1 labeling index and long-term outcome of visual pathway astrocytomas in children.

Although most visual pathway tumors are low-grade gliomas their biologic behavior is highly unpredictable. In order to determine whether assessment of proliferative activity can assist in predicting tumor behavior, we studied the MIB-1 labeling indices (MIB-1 LIs) in surgical specimens and monitored tumor growth in 31 consecutive children operated on between 1978 and 1997. The MIB-1 LIs at diagnosis varied from 0-10.6% (mean +/- SD, 3.27 +/- 2.49%). Tumor progression occurred in 19 patients leading to death in seven, three of whom had neurofibromatosis type 1 (NF1). No association between MIB-1 LI at initial diagnosis and both progression free and overall survival was apparent. However, the MIB-1 LIs increased to 15.2% and 18% in two patients with NF1 who developed highly malignant gliomas 6 and 6.5 years after irradiation. In the remaining patients the MIB-1 LIs did not change significantly over time in a total of 17 repeat surgeries. Three patients with LIs of 6.8%, 10.6% and 8.8% are stable after 6, 4.5 and 3.5 years with partial resection, biopsy and subtotal resection, respectively, and no further therapy in the first two and chemotherapy in the latter. Three patients (10%) with LIs of 6.4%, 4.8% and 2.2% either presented with or developed leptomeningeal spread during follow-up. While MIB-1 LI does not appear to assist in clinical decision making patient numbers were too small to find out whether response to chemotherapy varies with proliferative potential.

Adolescent↗
PubMed1999

Ancestral origins and worldwide distribution of the PRNP 200K mutation causing familial Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease (CJD) belongs to a group of prion diseases that may be infectious, sporadic, or hereditary. The 200K point mutation in the PRNP gene is the most frequent cause of hereditary CJD, accounting for >70% of families with CJD worldwide. Prevalence of the 200K variant of familial CJD is especially high in Slovakia, Chile, and Italy, and among populations of Libyan and Tunisian Jews. To study ancestral origins of the 200K mutation-associated chromosomes, we selected microsatellite markers flanking the PRNP gene on chromosome 20p12-pter and an intragenic single-nucleotide polymorphism at the PRNP codon 129. Haplotypes were constructed for 62 CJD families originating from 11 world populations. The results show that Libyan, Tunisian, Italian, Chilean, and Spanish families share a major haplotype, suggesting that the 200K mutation may have originated from a single mutational event, perhaps in Spain, and spread to all these populations with Sephardic migrants expelled from Spain in the Middle Ages. Slovakian families and a family of Polish origin show another unique haplotype. The haplotypes in families from Germany, Sicily, Austria, and Japan are different from the Mediterranean or eastern European haplotypes. On the basis of this study, we conclude that founder effect and independent mutational events are responsible for the current geographic distribution of hereditary CJD associated with the 200K mutation.

Amyloid↗
PubMed1999

Fatal familial insomnia: a new Austrian family.

We present clinical, pathological and molecular features of the first Austrian family with fatal familial insomnia. Detailed clinical data are available in five patients and autopsy in four patients. Age at onset of disease ranged between 20 and 60 years, and disease duration between 8 and 20 months. Severe loss of weight was an early symptom in all five patients. Four patients developed insomnia and/or autonomic dysfunction, and all five patients developed motor abnormalities. Analysis of the prion protein (PrP) gene revealed the codon 178 point mutation and methionine homozygosity at position 129. In all brains, neuropathology showed widespread cortical astrogliosis, widespread brainstem nuclei and tract degeneration, and olivary 'pseudohypertrophy' with vacuolated neurons, in addition to neuropathological features described previously, such as thalamic and olivary degeneration. Western blotting of one brain and immunocytochemistry in four brains revealed quantitative and regional dissociation between PrP(res)(the protease resistant form of PrP) deposition and histopathology. In the cerebellar cortex of one patient, PrP(res) deposits were prominent in the molecular layer and displayed a peculiar patchy and strip-like pattern with perpendicular orientation to the surface. In another patient, a single vacuolated neuron in the inferior olivary nuclei contained prominent intravacuolar granular PrP(res) deposits, resembling changes of brainstem neurons in bovine spongiform encephalopathy.

Adult↗
PubMed1999

A novel phenotype in familial Creutzfeldt-Jakob disease: prion protein gene E200K mutation coupled with valine at codon 129 and type 2 protease-resistant prion protein.

A novel phenotype of familial Creutzfeldt-Jakob disease (CJD) with mutated codon 200 of the prion protein gene (PRNP) coupled with the valine codon 129 (E200K-129V haplotype) has two features never observed in subjects carrying the pathogenic mutation coupled with the methionine codon 129 (E200K-129M haplotype): (1) plaque-like prion protein (PrP) deposits in the cerebellum and (2) type 2 protease-resistant prion protein (PrP(res)). This observation further underlines the role of codon 129 on the mutated PRNP allele in modulating the phenotype of familial prion diseases.

Aged↗
PubMed1999

Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects.

Phenotypic heterogeneity in sporadic Creutzfeldt-Jakob disease (sCJD) is well documented, but there is not yet a systematic classification of the disease variants. In a previous study, we showed that the polymorphic codon 129 of the prion protein gene (PRNP), and two types of protease-resistant prion protein (PrP(Sc)) with distinct physicochemical properties, are major determinants of these variants. To define the full spectrum of variants, we have examined a series of 300 sCJD patients. Clinical features, PRNP genotype, and PrP(Sc) properties were determined in all subjects. In 187, we also studied neuropathological features and immunohistochemical pattern of PrP(Sc) deposition. Seventy percent of subjects showed the classic CJD phenotype, PrP(Sc) type 1, and at least one methionine allele at codon 129; 25% of cases displayed the ataxic and kuru-plaque variants, associated to PrP(Sc) type 2, and valine homozygosity or heterozygosity at codon 129, respectively. Two additional variants, which included a thalamic form of CJD and a phenotype characterized by prominent dementia and cortical pathology, were linked to PrP(Sc) type 2 and methionine homozygosity. Finally, a rare phenotype characterized by progressive dementia was linked to PrP(Sc) type 1 and valine homozygosity. The present data demonstrate the existence of six phenotypic variants of sCJD. The physicochemical properties of PrP(Sc) in conjunction with the PRNP codon 129 genotype largely determine this phenotypic variability, and allow a molecular classification of the disease variants.

Adult↗
PubMed1998

Development of HIV encephalitis in AIDS and TNF-alpha regulatory elements.

Tumor necrosis factor-alpha (TNF-alpha) appears to play an important role in HIV encephalitis (HIVE). TNF2, a polymorphism of TNF-alpha, associates with higher levels of TNF-alpha and severe manifestations of some infections. We studied 44 acquired immunodeficiency syndrome (AIDS) patients with autopsy-proven HIVE and/or HIV leukoencephalopathy (HIVLE) (HIVE/LE) and 30 AIDS patients without HIVE/LE. TNF2 did not associate with presence of HIVE/LE (p > 0.5). Moreover, the TNF-alpha regulatory element TTATTTAT within the 3'-untranslated region was intact in HIVE/LE brains, and HLA-DR3 did not associate with HIVE/LE. Other host factors or, more likely, viral factors may be responsible for the development of HIVE/LE.

AIDS Dementia Complex↗
PubMed1998

[Creutzfeldt-Jakob disease in a dura transplant recipient: first observation in Austria].

Dura mater grafts can lead to Creutz-feldt-Jakob disease (CJD) as late complication (dura-CJD). So far 61 dura-CJD cases have been described worldwide. We report here the first dura-CJD case in Austria. A 50-year-old man had a traumatic open frontobasal skull fracture with tearing of dura mater in 1977. Reconstructive surgery used Lyodura (braun Melsungen AG, BRD). Lyodura was derived from pooled cadaveric dura. Ten years after the dural transplantation, the patient developed gait ataxia, paresthesia of both legs, myoclonus and visual disturbance. CT was unremarkable. EEG showed diffuse unspecific changes. The patient died 5 months after onset of disease. Neuropathological examination showed typical histopathology of CJD. Immunocytochemistry detected typical type prion protein (PrP) deposits and scattered PrP plaques in cerebral and cerebellar cortex, basal ganglia and spinal cord. Cerebellar white matter contained numerous PrP miniplaques. This pattern is unusual for sporadic CJD, but is similar to that in CJD after human growth hormone treatment. In our patient and 13/19 earlier described cases with dural graft covering the cerebrum ("central inoculation"), cerebellar disturbance was the initial symptom. Therefore, cerebellar signs are characteristic as initial symptoms in iatrogenic CJD, irrespective of central (cerebral dura mater graft) or peripheral inoculation (e.g., human growth hormone treatment). These data do not support the hypothesis that primary cerebellar symptoms in iatrogenic CJD after peripheral inoculation reflect migration of the infectious agent from the periphery via spinal cord and cerebellum to the cerebrum.

Brain↗
PubMed1998

Different patterns of truncated prion protein fragments correlate with distinct phenotypes in P102L Gerstmann-Sträussler-Scheinker disease.

The clinicopathological phenotype of the Gerstmann-Sträussler-Scheinker disease (GSS) variant linked to the codon 102 mutation in the prion protein (PrP) gene (GSS P102L) shows a high heterogeneity. This variability also is observed in subjects with the same prion protein gene PRNP haplotype and is independent from the duration of the disease. Immunoblot analysis of brain homogenates from GSS P102L patients showed two major protease-resistant PrP fragments (PrP-res) with molecular masses of approximately 21 and 8 kDa, respectively. The 21-kDa fragment, similar to the PrP-res type 1 described in Creutzfeldt-Jakob disease, was found in five of the seven subjects and correlated with the presence of spongiform degeneration and "synaptic" pattern of PrP deposition whereas the 8-kDa fragment, similar to those described in other variants of GSS, was found in all subjects in brain regions showing PrP-positive multicentric amyloid deposits. These data further indicate that the neuropathology of prion diseases largely depends on the type of PrP-res fragment that forms in vivo. Because the formation of PrP-res fragments of 7-8 kDa with ragged N and C termini is not a feature of Creutzfeldt-Jakob disease or fatal familial insomnia but appears to be shared by most GSS subtypes, it may represent a molecular marker for this disorder.

Adult↗
PubMed1998

Blood-brain barrier dysfunction in Binswanger's disease; an immunohistochemical study.

Binswanger's disease is pathologically characterized by a combination of diffuse cerebrovascular white matter lesions and lacunar infarcts in the basal ganglia and white matter. Although a blood-brain barrier (BBB) dysfunction has been implicated in the pathogenesis of these white matter (WM) lesions, few authors have addressed this problem. In the present study, we describe BBB dysfunction and its regional differences in the brains of Binswanger's disease patients. Twelve brains from Binswanger's disease patients (group III) were examined and compared with those from five patients with non-neurological disease (group I) and five cortical infarct patients without significant WM lesions (group II). Immunohistochemistry was performed for glial fibrillary acidic protein and vimentin as astroglial cell markers, and for immunoglobulins, complements and fibrinogen as extravasated serum protein markers. The grading scores for IgG extravasation were significantly higher in group III as compared to group I, in both the periventricular WM and the subcortical WM (P < 0.01). In group III, the scores in the periventricular WM and subcortical WM were significantly higher than in the subcortical U fibers and cerebral cortex (P < 0.01 for the periventricular WM; P < 0.001 for the subcortical WM), respectively. Clasmatodendritic astroglia, which had swollen cell bodies and large cytoplasmic vacuoles with disintegrated processes, incorporated the serum components IgG, IgM, C3d, Clq and fibrinogen, both in the periventricular WM and subcortical WM in 5 out of 12 (42%) Binswanger's disease brains. These results indicate that WM lesions in Binswanger's disease are accompanied by BBB dysfunction, although it remains uncertain whether BBB dysfunction is secondary to either chronic cerebral ischemia or arterial hypertension.

Aged↗
PubMed1998

Coexistence of Alzheimer-type neuropathology in Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease (CJD) and Alzheimer's disease (AD) share clinical, neuropathological, and pathogenetic features. To investigate eventual mutual influences, we screened prominently affected neocortex from 110 neuropathologically proven CJD patients for Alzheimer-type pathology with anti-beta/A4, Bielschowsky and anti-tau (immuno)stains. The neuropathological classification of Alzheimer-type pathology was made according to the CERAD criteria. Results were controlled by comparison with Alzheimer-type changes in sections from the same cortical areas in 110 sex- and age-matched non-demented control patients. For comparison, the control patients were also classified according to the CERAD neuropathology criteria as if they had been demented. Alzheimer-type tissue changes as in definite and probable CERAD AD occur in 10.9% of the CJD patients and 19.1% of control patients (P=0.11). The median age of CJD and control patients with CERAD AD is 72 and 68 years, respectively, which differs significantly from the median ages of 64 and 63 years, respectively, in the non-AD/CJD and non-AD control patients. Since CERAD criteria include "presence of other neuropathological lesions likely to cause dementia", an AD diagnosis in CJD patients (all of whom are demented) is solely based on densities of neuritic plaques. Similar Alzheimer-type changes in even higher frequency, however, are also present in elderly non-demented controls. Thus, the coexistence of Alzheimer-type pathology in CJD most likely represents an age-related change. Deposits of prion protein (PrP) frequently accumulate at the periphery of beta/A4 plaques. The presence of beta/A4 amyloid in the brain may influence PrP morphogenesis.

Aged↗
PubMed1998

Neuronal apoptosis in fatal familial insomnia.

The possibility that neuronal loss in prion diseases occurs through an apoptotic process has been postulated and is consistent with the lack of inflammation in these disorders. In order to test this hypothesis in FFI, in which neuronal loss is the predominant neuropathological feature, we examined samples of thalamus, basal ganglia, cerebral cortex, cerebellum and medulla from 10 subjects with FFI. All the patients had the characteristic 178 N mutation of the PrP gene. Eight subjects were homozygous methionine/methionine at codon 129 and 2 were heterozygous methionine/valine. Apoptotic neurons were identified by in situ end labelling in all the FFI cases and in none of the controls. They were mostly found in damaged regions and their presence and abundance seemed to correlate closely with the neuronal loss. They were particularly abundant in the thalamus and medullary olives. In heterozygous cases who had a longer disease duration and more widespread cerebral changes, apoptotic neurons were also found in the neocortex and striatum. The abundance of apoptotic neurons also correlated well with microglial activation as demonstrated by the expression of major histocompatibility complex class II antigens. PrPres immunostaining was almost invariably negative, consistent with previous data showing the lack of obvious correlation between neuronal loss and PrPres deposits in prion diseases.

Adult↗
PubMed1998

Severe, early and selective loss of a subpopulation of GABAergic inhibitory neurons in experimental transmissible spongiform encephalopathies.

Little is known about the pathogenetic basis of characteristic symptoms in transmissible spongiform encephalopathies (TSEs) such as myoclonus and characteristic EEG hyperactivity. We investigated the GABAergic system and its subpopulations in mice inoculated with experimental scrapie (ME7, RML, 22A strains) and Creutzfeldt-Jakob disease (CJD; Fujisaki strain), to study damage to inhibitory neurons. Since recent studies have shown electrophysiological changes in prion protein (PrP) knockout mice, we also studied mice lacking or overexpressing the PrP gene. Antibodies against glutamic acid decarboxylase (GAD), parvalbumin (PV), calbindin (CB), and calretinin (CR) were used to stain GABAergic neurons, and isolectin-B4 to stain perineuronal nets around PV+ neurons. In scrapie infected mice, cortical PV+ neurons were severely reduced while CB+ and CR+ neurons were well preserved. In CJD inoculated mice, loss of PV+ neurons was severe and occurred very early after inoculation. PrP-/- and tg20 mice showed normal appearance of PV, CB, CR, GAD+ neurons and their neuropil, and of isolectin-B4+ perineuronal nets. The early, severe and selective loss of cortical PV+ neurons in experimental scrapie and CJD suggest selective loss of PV+ GABAergic neurons as important event during disease development, possibly as one basis of excitatory symptoms in TSEs.

Animals↗