Selective neuronal vulnerability in human prion diseases. Fatal familial insomnia differs from other types of prion diseases.

Human transmissible spongiform encephalopathies (TSEs) or prion diseases are neurodegenerative disorders of infectious, inherited or sporadic origin and include Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), kuru and fatal familial insomnia (FFI). Clinicopathologic features of FFI differ markedly from other human TSEs. Previous studies demonstrated selective neuronal vulnerability of parvalbumin positive (PV+) GABAergic inhibitory interneurons in sporadic CJD and experimental TSEs.

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.

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.

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.

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.

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.

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.

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.

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.

Cytopathological alterations and therapeutic approaches in Binswanger's disease.

Binswanger's disease (BD) is a condition characterized by prominent brain atrophy with ventricular dilatation, diffuse white matter (WM) lesions and a scattering of lacunar infarcts. BD patients have dementia, and have vascular risk factors, focal cerebrovascular deficits and evidence of subcortical cerebral dysfunction. From our clinical studies, the most effective prophylaxis against the development of BD is to manage the hypertension, especially a high nocturnal blood pressure, in the early stage patients showing only a scattering of lacunes and/or mild WM lesions.

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.

[Stereotactic brain biopsy in AIDS patients: a necessary patient-oriented and cost-effective diagnostic measure?].

Neurological complications occur in 40% of "human immunodeficiency virus type 1" (HIV-1)-infected patients. Aim of the study was to evaluate the diagnostic yield of stereotactic brain biopsy and non invasive diagnostic procedures (CT, antitoxoplasma antibodies) and to calculate the benefit of the brain biopsy for the patient and the costs of both methods. From October 1989 through September 1995 we biopsied 44 of 2749 (2%) HIV-1-infected patients after non invasive diagnostic procedures had been performed.

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.

[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.

Malnutrition-induced hypokalemic myopathy in chronic alcoholism.

A 42-year-old man with a history of Billroth II-gastrectomy, chronic alcoholism, and malnutrition developed acute tetraparesis, two days before admission. He presented with bilateral, proximal upper and lower limb weakness, limb girdle wasting, bilaterally reduced Achilles tendon reflexes, and bilateral stocking-type sensory disturbances. Laboratory data revealed hypokalemia (2.

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.

Fatal familial insomnia around the world. Introduction.

Despite decades of research, much intensified in recent years, transmissible spongiform encephalopathies (TSEs) or prion diseases have remained enigmatic in many aspects. Among these, the intricate connection between infectivity and genetics, genotype-phenotype correlation, and pathogenesis of brain damage are major problems in need of clarification. Fatal familial insomnia (FFI) appears as an ideal model situation for answering some of these problems: it has been understood to have a distinctive clinicopathological phenotype based on a specific genotype as well as transmissibility.

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.

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.

[Epidemiology of transmissible spongiform encephalopathies (prion diseases) in Austria].

Between 1969 and 1996, transmissible spongiform encephalopathy was definitely diagnosed by autopsy and/or biopsy in 98 Austrian patients. The yearly incidence increased significantly in past years (1996: 1.41 cases per million inhabitants).

[Cerebrospinal fluid diagnosis of Creutzfeldt-Jakob disease].

Diagnosis of Creutzfeldt-Jakob disease (CJD) at lifetime according to the international diagnostic criteria may be greatly improved by the additional assay of 14-3-3 protein in cerebrospinal fluid (CSF). Occurrence of 14-3-3 protein in CSF may be observed in etiologically different conditions of brain damage, but confers high diagnostic specificity in cases of suspected CJD based on the diagnostic criteria. We investigated the occurrence of 14-3-3 protein in CSF of 20 patients with an accompanying diagnosis "suspected CJD", of whom 5 cases had to be classified as neither probable nor possible CJD according to the international diagnostic criteria, as well as in 18 control cases with diseases other than CJD.

[Transmissible spongiform encephalopathies--illnesses in the human].

Transmissible spongiform encephalopathies (TSEs) or prion diseases in man and animals are of utmost interest at present. Reasons are the highly probable origin from BSE of a new variant of Creutzfeldt-Jakob disease (CJD) in the UK and France, the new paradigm in biomedicine of the association of heredity and transmissibility, and the possible propagation of infectivity by protein only according to the prion hypothesis. Determination of the 14-3-3 protein in CSF and magnetic resonance imaging are promising new diagnostic tools; however, clinical examination yields only a suspect diagnosis, with formal criteria for "probable" or "possible" CJD.