Ultrastructural characteristics (or evaluation) of Creutzfeldt-Jakob disease and other human transmissible spongiform encephalopathies or prion diseases.

The authors report on a large series of human prion diseases to establish ultrastructural characteristics that may be useful for their diagnosis. For Creutzfeldt-Jakob disease (CJD and its variant, vCJD) and fatal familial insomnia (FFI) only vacuolation (spongiform change) and the presence of tubulovesicular structures are consistent findings. Other changes, such as the presence of myelinated vacuoles, branching cisternae, neuroaxonal dystrophy, and autophagic vacuoles, were present in different proportions in either CJD or FFI, but they are nonspecific ultrastructural findings that can also occur in other neurodegenerative conditions.

Tubulovesicular structures are a consistent (and unexplained) finding in the brains of humans with prion diseases.

Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS) and Fatal Familial Insomnia (FFI) are slow neurodegenerative disorders classified as transmissible spongiform encephalopathies (TSEs) or prion diseases, which appear in sporadic, hereditary or environmentally acquired forms. Tubulovesicular structures (TVS) are ultrastructural particles of unknown origin and chemical composition found in the brains of both animal and human forms of transmissible spongiform encephalopathies or prion diseases. In this paper, we report the results of a search for TVS in a total of 13 cases of sporadic Creutzfeldt-Jakob disease, three cases of Gerstmann-Sträussler-Scheinker disease, two cases of Fatal Familial Insomnia, and individual cases of familial, iatrogenic, and variant CJD (vCJD).

Variations of the ultrastructure of neuronal lipofuscin during childhood and adolescence in the human Ammon's horn.

The ultrastructure of lipofuscin (Lf) was studied in hippocampal and neocortical neurons of children and youngsters between 3 months and 24 years of age. As a standard, regions CA1 and CA4 of Ammon's horn and the gyrus centralis anterior of the left hemisphere were examined, and the ratio of the two components of Lf, the pigment part, and the usually droplet-like lipid part was looked at. Few and small granules with typical linear structures in the pigment part and little lipid droplets were found as early as at the age of 3 months in all brain regions.

Species-specific ultrastructure of neuronal lipofuscin in hippocampus and neocortex of subhuman mammals and humans.

Lipofuscin represents an integral part of neurons and glial cells in mammals and in submammalian species. It is a special lysosomal organelle, takes part of cellular metabolism, and is a structural expression of catabolic pathways. Species-specific differences of lipofuscin indicate metabolic differences of the relevant neurons.

Gerstmann-Sträussler-Scheinker disease- the dilemma of molecular and clinical correlations.

Gerstmann-Sträussler-Scheinker disease (GSSD) is a hereditary as well as transmissible human prion disease, restricted to families carrying point mutations of the PRPN gene on chromosome 20. To date 7 different causative mutations have been found. In this review the results of molecular biology with regard to the clinical course are discussed.

Gerstmann-Sträussler-Scheinker disease with A117V mutation in a second French-Alsatian family.

We report a kindred of French/Alsatian origin with symptoms of Gerstmann-Sträussler-Scheinker disease over 3 generations. In the propositus, cerebellar signs and memory disturbance were the presenting features, followed by other neurological manifestations. Biopsy of the cerebral cortex showed numerous multicentric and "kuru"-type amyloid plaques that on immuno-light and electron microscopy stained with antibody to prion protein.

Microglia is a component of the prion protein amyloid plaque in the Gerstmann-Sträussler-Scheinker syndrome.

The microglial cell has been demonstrated as component of the cerebral amyloid plaque of Alzheimer's disease. Involvement of microglia in plaques of another cerebral amyloidosis, the Gerstmann-Sträussler-Scheinker syndrome (GSS), has found little attention. We examine here the presence of microglia in GSS plaques by immunohistochemistry and transmission electron microscopy.

Miniplaques and shapeless cerebral amyloid deposits in a case of Gerstmann-Sträussler-Scheinker's syndrome.

Multicentric plaques of typical pathomorphology have been described in two members of the well-documented German family "Sch" with Gerstmann-Sträussler-Scheinker's syndrome (GSS). The case of a third affected member with a clinical course of 10 years is now reported. In addition to multicentric plaques, small granules of prion protein (PrP) with stellate ultrastructure (miniplaques) were found in the tractus perforans and alveus of the hippocampal area.

Creutzfeldt-Jakob disease with amyloid angiopathy: diagnosis by immunological analyses and transmission experiments.

It was difficult to make a definite pathological diagnosis in a 73-year-old man with Creutzfeldt-Jakob disease (CJD) due to extensive amyloid angiopathy which lacked any severe spongiform changes. Immunostaining using anti-prion protein (PrP) antibody revealed fine granular deposits in the gray matter, after hydrolytic autoclaving pretreatment on tissue sections. Western blotting also revealed an abnormal isoform of PrP, but PrP gene analysis did not show any abnormalities.

Clinical and molecular genetic study of a large German kindred with Gerstmann-Sträussler-Scheinker syndrome.

We have verified, by full open reading frame sequencing, the presence of an amino-acid-altering mutation in codon 102 of the scrapie amyloid protein gene in three affected members of a large and well-documented German family with experimentally transmitted Gerstmann-Sträussler-Scheinker syndrome. In addition, we identified the mutation by partial sequencing or DNA restriction enzyme analysis in three of 12 presently healthy family members with an affected parent, and none of 12 members without an affected parent. Thus, a total of six of 15 family members at risk for the disease (including the three established cases) had the same codon 102 mutation, a proportion consistent with the autosomal dominant inheritance pattern of disease expression.

Neuronal autophagy in experimental scrapie.

In this study we report the formation of giant autophagic vacuoles (AV) in neurons in experimental scrapie in hamsters. Autophagy is an important step in the cellular turnover of proteins and organelles. It is known to occur in neurons under physiological as under pathological conditions.

Creutzfeldt-Jakob disease and kuru patients lack a mutation consistently found in the Gerstmann-Sträussler-Scheinker syndrome.

We and others have recently reported that patients with the Gerstmann-Sträussler-Scheinker syndrome have a mutation at codon 102 of the gene coding for amyloid protein that accumulates in this disease. We report here that this mutation was not found in 5 familial and 27 sporadic cases of Creutzfeldt-Jakob disease or in 3 patients with kuru, so that although this mutation may be responsible for amyloidogenesis and transmissibility in Gerstmann-Sträussler-Scheinker syndrome, it cannot be the only cause of human spongiform encephalopathy.

Immunogold light and electron microscopic detection of amyloid plaques in transmissible spongiform encephalopathies.

The antigenicity of the 'prion' protein amyloid fibrils was shown to be preserved after glutaraldehyde/OsO4 fixation in uranyl acetate-stained brain tissue blocks from patients with Gerstmann-Sträussler syndrome (GSS) and from mice infected with Creutzfeldt-Jakob disease (CJD). Amyloid plaques were demonstrated by light microscopy in immunogold silver-intensified semithin sections. Under the electron microscope, the amyloid fibrils were labelled in immunogold-reacted ultrathin sections using an antiserum prepared against GSS amyloid plaque cores and mouse amyloid fibrils respectively.

Neuronal autophagy in experimental Creutzfeldt-Jakob's disease.

We report an experimental model of Creutzfeldt-Jakob's disease (CJD) in mice leading to the formation of giant autophagic vacuoles (AV) in neurons of the cerebral cortex. These AV appear at the end of the incubation period (4-6 months postinoculation), together with spongy changes and clinical symptoms. Autophagy, a process of intracellular digestion of cell constituents by the lysosomal compartment, is known in many cell types, where it plays a role both in the physiological turnover and in pathological processes and is involved in protein metabolism.

Ultrastructural heterogeneity of neuronal lipofuscin in the normal human cerebral cortex.

The ultrastructure of the age pigment in neurons of the normal human isocortex was investigated in seven autopsies and two biopsies. In the autopsies four cortical areas of Brodmann, viz. 6, 7, 11 and 17 were studied.

Acid phosphatase activity in human neuronal and glial lipofuscin.

The ultrastructural demonstration of acid phosphatase activity in neuronal and glial lipofuscin of the aged human brain indicates lysosomal activity. Contrary to the constantly high enzyme activity of astroglial lipofuscin and low activity of oligodendroglial lipofuscin, the enzyme activity of neuronal pigment differs in different locations, i.e.

Experimental transmission of human subacute spongiform encephalopathy to small rodents. IV. Positive transmission from a typical case of Gerstmann-Sträussler-Scheinker's disease.

Spongiform encephalopathy was transmitted to mice from a patient belonging to the "Sch" family with Gerstmann-Sträussler-Scheinker's disease (GSS). Incubation periods in the first passage were much shorter than those in mice infected with Creutzfeldt-Jakob disease. Clinical and pathologic findings of mice infected with both diseases were almost identical.

[Morbus Gerstmann-Sträussler-Scheinker. The Sch. family-a report of three cases (author's transl)].

The clinical symptoms from three cases and histological findings from two patients suffering from morbus Gerstmann-Sträussler-Scheinker (M-GSS) are reported. This disease belongs to the group of subacute spongiform encephalopathies. It is extremely rare and so far has only been observed in 52 members of four large families, in which the symptoms begin between the age of 33 and 50 and lead to death in 4-5 years.

Gerstmann-Sträussler-Scheinker's disease. Electron-microscopic observations on a brain biopsy.

Light and electron microscopic observations are reported on a brain biopsy of a man of 59 with a rare familial disease of the CNS and a 5-year clinical course. Electron micrographs of the frontal biopsy reveal plaque-like deposits composed of amyloid cores, often multicentric in the cortex and subcortical white matter. They are localized between enlarged astrocytic processes.

[Subacute spongiform encephalopathy with multiform plaque formation. "Peculiar familial-hereditary disease of CNS [spinocerebellar atrophy with dementia, plaques, and plaque-like deposits in cerebellum and cerebrum" (Gerstmann, Sträussler, Scheinker)] (author's transl)].

Report of two unrelated cases of a rare familiar disease of degenerative nature, from a clinical point of view belonging to the spinocerebellar atrophies, combined with dementia. According to the pedigrees, the disease can be followed up to 3--4 generations. Microscopic study reveals glioneuronal dystrophy with spongiform changes together with kuru plaques and atypical plaque-like formations, hitherto only described in this disease.

[Basilar or vertebral artery aneurysm as a cause of presumed cervical spine injury (author's transl)].

The characteristic clinical features and morphological findings of five cases of (clinically not diagnosed) fusiform aneurysm of the basilar or vertebral arteries were recurring attacks of positional occipital headache, pain and stiffness in the neck, cranial nerve disturbances, expecially oculomotor palsies and anisokoria, nystagmus, attacks of nausea, vomiting and sweating, tachycardia, pyramidal tract symptoms, and pareses. Severe hypertension had been present in four instances. The aneurysm, which is usually thrombosed, pressed against the pons and medulla oblongata as a space-occupying mass.