Human Spongiform Encephalopathies Research Articles

The "brave new world" of transmissible spongiform encephalopathy (infectious cerebral amyloidosis).

The story of transmissible human spongiform encephalopathy, from its origins to the present time, enjoys the commentary of a cast of characters from Shakespeare's imaginary island in The Tempest, with a brief visit to the real island of Tasmania for a bird's eye view of the prion, and some concluding thoughts about the current state of research in the netherworlds of molecular biology and physical chemistry.

Developments in diagnosis for prion diseases

The protease resistant isoform of prion protein (PrP) is a diagnostic marker of spongiform encephalopathies in humans and animals. Immunoblotting is a sensitive method but requires either fresh or frozen, unfixed materials. Immunohistochemistry using formalin-fixed, paraffin-embedded materials is now also considered to be sensitive and comparable to immunoblotting after various treatments, especially using the hydrolytic autoclaving method on tissue sections before staining. The advantage of this method is that it can be applied to routine pathology materials or long preserved materials. The kuru plaque-type deposition of PrP suggests abnormalities of the PrP gene, while synaptic-type deposition suggests either sporadic CJD or particular familial CJD. PrP gene abnormalities are thus related to PrP deposition and modify clinical symptoms and their progression. A PrP gene analysis can be done using either preclinical, clinical or post-mortem materials.

Neuropathology of spongiform encephalopathies in humans

The historical aspects and classification of human spongiform encephalopathies are reviewed and the newer concept of 'prion dementias' is explored. Guidelines for safe laboratory and autopsy handling of spongiform encephalopathy tissues are outlined: this includes an update on strategies which are currently thought to be effective in decontamination. A wide ranging review of the pathology of the various human spongiform encephalopathies includes newly emerging data on microglia, and cell-specific and neurodegenerative proteins. A large section of this chapter is devoted to the methodology of immunocytochemical demonstration of PrP in tissue sections, and the dilemmas inherent in interpretation. Clinicopathological correlations are provided for classical cases of spongiform encephalopathy, together with the newly recognised atypical dementias associated with PrP gene mutations. The pathology of iatrogenic cases of CJD is described. The chapter concludes with problems in differential diagnosis, and discussion of the histopathological features which help to resolve diagnostic dilemmas.

Localization of the mRNA for a chicken prion protein by in situ hybridization.

The infectious agent (prion) responsible for transmissible spongiform encephalopathies in humans and animals is composed primarily of a 33- to 35-kDa glycoprotein called PrPSc (scrapie isoform of prion protein), which is a posttranslationally modified form of the normal cell-surface protein PrPC. Little is known about the function of PrPC. Interestingly, chPrP, the chicken homologue of PrPC, copurifies with a factor from brain that stimulates synthesis of acetylcholine receptors on skeletal muscle cells. Using in situ hybridization, we report here that chPrP mRNA is widely distributed in cholinergic and noncholinergic neurons throughout the adult central nervous system, including those in the telencephalic striata, thalamus and hypothalamus, optic tectum, medulla, cerebellum, and spinal cord. The mRNA is present in the brain and spinal cord as early as embryonic day 6 and is also found in dorsal root ganglia, retina, intestine, and heart. Our data suggest that if chPrP serves to regulate acetylcholine receptor number on postsynaptic targets, this is not its only function. It is likely that the protein plays a more widespread role in the central nervous system and perhaps elsewhere, possibly one related to intercellular communication, adhesion, or recognition. The chicken embryo represents an attractive experimental system in which to investigate the normal developmental function of PrPC.

Ubiquitin immunocytochemistry in human spongiform encephalopathies.

The distribution of ubiquitin was studied by immunocytochemistry in eight cases of human spongiform encephalopathy and compared with the findings in seven age- and sex-matched cases of Alzheimer's disease and six non-demented control cases. The results were also compared with the immunocytochemical distribution of prion protein and the lysosomal aspartic protease cathepsin D. In the human spongiform encephalopathies, ubiquitin immunoreactivity was found in a punctate distribution at the periphery of prion protein amyloid plaques and in a finely granular pattern in the neuropil around and within areas of spongiform change. Cortical nerve cells contained scanty ubiquitinated dot-like inclusions, and occasional microglia around the areas of spongiform change also gave a positive staining reaction for ubiquitin, as did multiple irregular thread-like structures in the neuropil and white matter. The ubiquitin-containing structures at the plaque periphery in human spongiform encephalopathies resemble the neuritic processes at the periphery of the senile plaque in Alzheimer's disease. The granular positivity for ubiquitin associated with areas of spongiform change closely resembles the pattern of immunostaining seen with the antibodies to the prion protein and cathepsin D, consistent with the reported accumulation of ubiquitinated proteins and prion protein in lysosomes in the murine scrapie model. Further studies are required to investigate the role of lysosomes in this group of disorders, and to study the localization of other cell stress proteins and prion protein in spongiform encephalopathies.

Human prion diseases (spongiform encephalopathies).

Prion diseases (spongiform encephalopathies) in humans are Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and kuru. Clinically, they are characterized by an inexorably progressing neurological illness with dementia and ataxia as the most prominent signs. The classical neuropathological changes are limited to the central nervous system and consist of spongiform degeneration, amyloid plaques, astrocytic gliosis, and nerve cell loss. The human spongiform encephalopathies, which for many years were considered neurodegenerative disorders of unknown etiology, were finally recognized as transmissible diseases similar to scrapie in sheep in the late 1960's. The infectious agent appears to consist of protein devoid of functional nucleic acid and has been termed prion to distinguish it from viruses. The prion hypothesis has gained wide acceptance through the finding that mutations of the prion protein gene are associated with heritable human prion disease. Different mutations appear to cause prion disease with a distinct pattern of clinical and pathological features in a great number of families. Certain mutations of the PrP gene have been shown to be associated with clinical and neuropathological changes not typical of any variant of human prion disease known to date. A new classification of prion diseases based on the molecular biology and biochemistry of the prion protein is likely to emerge.

Neuropathology of Chronic Wasting Disease of Mule Deer (Odocoileus hemionus) and Elk (Cervus elaphus nelsoni)

The pathology of the central nervous system of nine mule deer (Odocoileus hemionus) and six elk (Cervus elaphus nelsoni) with chronic wasting disease, a spongiform encephalopathy of mule deer and elk, was studied by light microscopy. Lesions were similar in both species and were characterized by spongiform transformation of gray matter, intracytoplasmic vacuolation of neurons, neuronal degeneration and loss, astrocytic hypertrophy and hyperplasia, occurrence of amyloid plaques, and absence of significant inflammatory response. Distribution and severity of lesions were evaluated at 57 locations; there were only minor differences between deer and elk. Consistent, severe lesions occurred in olfactory tubercle and cortex, hypothalamus, and the parasympathetic vagal nucleus of deer, and sections examined from these regions would be sufficient to establish a diagnosis of chronic wasting disease. Lesions were milder in these locations in elk but were sufficiently apparent to be of diagnostic value. Other differences included increased severity of lesions in some thalamic nuclei in elk in contrast to deer, the occurrence of amyloid plaques demonstrable by hematoxylin and eosin and histochemical stains in deer in contrast to elk, and the presence of mild white matter lesions in elk but not in deer. Lesions of chronic wasting disease were qualitatively comparable to those of scrapie, bovine spongiform encephalopathy, transmissible mink encephalopathy, and the human spongiform encephalopathies. Topographic distribution and lesion severity of chronic wasting disease were most similar to those of scrapie and bovine spongiform encephalopathy. Duration of clinical disease did not significantly influence lesion distribution or severity in either species.

Surveillance for lesions of bovine spongiform encephalopathy in US cattle.

In October 1987, bovine spongiform encephalopathy (BSE) was described in Great Britain as a novel disease of cattle with neurologic lesions comparable to those of scrapie in sheep and other spongiform encephalopathies of animals and humans. Cases in adult cattle occurred with increasing frequency primarily in southern England during the next several months, and there are approximately 600 new cases each week in Great Britain? Epidemiologic studies incriminated the feeding of rations containing ruminant-derived protein, especially to calves. The prolonged incubation period was similar to that observed in scrapie. The presence in the United States of scrapie and other animal spongiform encephalopathies (transmissible mink encephalopathy and chronic wasting disease of mule deer and elk) provided impetus to survey US cattle for lesions of BSE. A cooperative project between the US Department of Agriculture (USDA), Animal Plant Health Inspection Service (APHIS), Science and Technology, National Veterinary Services Laboratories (NVSL), and the Iowa State University, Department of Veterinary Pathology, was initiated in May 1990 with the goal of examining brain specimens from 250 suspect cattle. Beginning in May 1990, formalin-fixed brain specimens or microscope slides from BSE-suspect cattle were requested, and in April 1991, the project was expanded to include referred cases submitted for rabies examination and found not to be rabies. The criteria used to classify cases as BSE suspects are cattle that (1) are ≥2 years old, (2) have documented signs of neurologic disease, and (3) have received protein supplement as a substantial part of the ration. Specimens are shipped to the NVSL, Ames, Iowa, in standard cartons via US Postal Service or commercial transport systems. Fixed brain specimens are referred to the Iowa State University, Department of Veterinary Pathology, for further processing. Blocks of tissue from 12 areas, if available, are selected as follows: frontal cortex, corpus striatum, temporal cortex, optic chiasm, occipital cortex with hippocampus, thalamus, mesencephalon, pons, cerebellum, rostra1 medulla, obex, and caudal medulla. Tissue blocks are processed by routine methods, embedded in paraffin, sectioned at 8 μm, mounted on glass microscope slides, and stained with hematoxylin and eosin. Special stains, such as Brown-Hopps Gram stain, luxol fast blue-cresyl echt violet, and glial fibrillary acidic protein, are used as needed. Evaluation of the morphology is based on light microscopy.

CDNA cloning of a novel heterogeneous nuclear ribonucleoprotein gene homologue in Caenorhabditis elegans using hamster prion protein cDNA as a hybridization probe.

The mammalian prion protein (PrPc) is a cellular protein of unknown function, an altered isoform of which (PrPsc) is a component of the infectious particle (prion) thought to be responsible for spongiform encephalopathies in humans and animals. The evolutionary conservation of the PrP gene has been reported in the genomes of many vertebrates as well as certain invertebrates. In the genome of nematode Caenorhabditis elegans, the sequence capable of hybridizing with the mammalian PrP cDNA probe has been demonstrated, predicting the presence of the PrP gene homologue in C.elegans. In this study, Southern analysis with the hamster PrP cDNA (HaPrP) probe confirmed the previous observation. Moreover, Northern analysis revealed that the sequence is actively transcribed in adult worms. Thus, we screened C.elegans cDNA libraries with the HaPrP probe and isolated a cDNA that hybridizes to the same sequence in C.elegans that hybridized with the HaPrP probe in the Southern and Northern analyses. The deduced amino acid sequence of this cDNA, however, is substantially homologous with heterogeneous nuclear ribonucleoprotein (hnRNP) core proteins rather than mammalian PrPc. The hnRNPs contain the glycine-rich domain in the C-terminal half of the molecule, which also seemed to be in PrPc at the N-terminal half of the molecule. Both of the glycine-rich domains are composed of tracts with high G + C content, indicating that these tracts may due to the hybridizing signals. These results suggest that this cDNA clone is derived from a novel hnRNP gene homologue in C.elegans but not from a predicted PrP gene homologue.

A prion-like protein from chicken brain copurifies with an acetylcholine receptor-inducing activity.

The mammalian prion protein (PrPC) is a cellular protein of unknown function, an altered isoform of which (PrPSc) is a component of the infectious particle (prion) thought to be responsible for spongiform encephalopathies in humans and animals. We report here the isolation of a cDNA that encodes a chicken protein that is homologous to PrPC. This chicken prion-like protein (ch-PrLP) is identical to the mouse PrP at 33% of its amino acid positions, including an uninterrupted stretch of 24 identical residues, and it displays the same structural domains. In addition, ch-PrLP, like its mammalian counterpart, is attached to the cell surface by a glycosyl-phosphatidylinositol anchor. We find that ch-PrLP is the major protein in preparations of an acetylcholine receptor-inducing activity that has been purified greater than 10(6)-fold from brain on the basis of its ability to stimulate synthesis of nicotinic receptors by cultured myotubes. The ch-PrLP gene is expressed in the spinal cord and brain as early as embryonic day 6; and in the spinal cord, the protein appears to be concentrated in motor neurons. Our results therefore raise the possibility that prion proteins serve normally to regulate the chemoreceptor number at the neuromuscular junction and perhaps in the central nervous system as well.

Risk of Creutzfeldt-Jakob disease in relation to animal spongiform encephalopathies: A collaborative study in Europe

This paper describes a study of the risk of Creutzfeldt-Jakob disease in various European countries. The objectives of the study are to investigate the frequency of Creutzfeldt-Jakob disease and other human spongiform encephalopathies in Europe in relation to animal spongiform encephalopathies, and to assess the risk of Creutzfeldt-Jakob disease in relation to genetic, occupational and nutritional factors. The study will consist of three parts: the establishment of registries of Creutzfeldt-Jakob disease on the basis of cases in the registries, and molecular genetic studies with material collected in the registries.

Clinical, laboratory, and morphological diagnosis of human subacute spongiform encephalopathies in byelorussia

Clinical, laboratory, and morphological diagnosis of human subacute spongiform encephalopathies in byelorussia

Prion diseases in man

Human spongiform encephalopathies (HSE) are uncommon neurodegenerative diseases of unknown etiology. Whilst numerous observations provide arguments for an infectious disorder mediated by an unconventional agent of the so-called prion-type, the recent discovery of predisposing allelic variants suggests that HSE might be considered as genetically linked diseases.

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.

Experimental Scrapie in White Swiss Mice

In order to confirm the clinical and histological diagnosis of scrapie and to determine the infectivity titer of the scrapie agent in the brain of a naturally infected Suffolk sheep, 123 white Swiss mice were inoculated intracerebrally. From about 13 to 20 months post-inoculation, 28 mice died, and 95 that were sick were killed. In the terminal stages of disease, the mice developed weakness, gradual emaciation, posterior ataxia, and occasionally alopecia. The average infection (83%) of mice affected with scrapie occurred in groups 1 to 4 inoculated with dilution 10(-1) to 10(-4) of scrapie sheep brain. Sixty-seven (54.5%) of the mice developed spongiform lesions and vacuolar degeneration of neurons. Similarities of scrapie with other subacute spongiform encephalopathies in animals and humans are discussed.

Sheep consumption: a possible source of spongiform encephalopathy in humans

A fatal spongiform encephalopathy of sheep and goats (scrapie) shares many characteristics with Creutzfeldt-Jakob disease (CJD), a similar dementing illness of humans. To investigate the possibility t

Sheep consumption: a possible source of spongiform encephalopathy in humans.

A fatal spongiform encephalopathy of sheep and goats (scrapie) shares many characteristics with Creutzfeldt-Jakob disease (CJD), a similar dementing illness of humans. To investigate the possibility that CJD is acquired by ingestion of contaminated sheep products, we collected information on production, slaughtering practices, and marketing of sheep in Pennsylvania. The study revealed that sheep were usually marketed before central nervous system signs of scrapie are expected to appear; breeds known to be susceptible to the disease were the most common breeds raised in the area; sheep were imported from other states including those with a high frequency of scrapie; use of veterinary services on the sheep farms investigated and, hence, opportunities to detect the disease were limited; sheep producers in the area knew little about scrapie despite the fact that the disease has been reported in the area, and animal organs including sheep organs were sometimes included in processed food. Therefore, it was concluded that in Pennsylvania there are some 'weak links' through which scrapie-infected animals could contaminate human food, and that consumption of these foods could perhaps account for spongiform encephalopathy in humans. The weak links observed are probably not unique to Pennsylvania.

Experimental transmission of human subacute spongiform encephalopathy to small rodents. II. Ultrastructural study of spongy state in the gray and white matter.

Light and electron microscopic findings of spongy state in four species of small rodents, viz, mice, rats, Mongolian gerbils, and guinea pigs, are described. The spongy state existed in both gray and white matter; its intensity varied in each species, and in the gray matter corresponded to vacuoles within the neuropil. They were of two types; one was the true vacuoles within neurites, and the other was markedly swollen cell processes, some of which were also identified as neurites. In the white matter, the spongy state corresponded mainly to distension of the myelin sheaths, due to splitting of the major dense line or swelling of the inner loop, and partly to intra-axonal vacuoles. In mice before appearance of clinical symptoms, the vacuolation occurred first in the cerebral white matter 5 weeks after inoculation and in the cerebral cortex at 7 weeks. The occurrence and development of the vacuoles are discussed.

CREUTZFELDT-JAKOB DISEASE

Journal Article CREUTZFELDT-JAKOB DISEASE: THE NEUROPATHOLOGY OF A TRANSMISSION EXPERIMENT Get access ELISABETH BECK, ELISABETH BECK Department of Neuropathology, Institute of Psychiatry, The Maudsley HospitalLondon, S.E.5 The Derbyshire Royal InfirmaryDerby and National Institutes of HealthBerhesda, Maryland, U.S.A. Search for other works by this author on: Oxford Academic PubMed Google Scholar P. M. DANIEL, P. M. DANIEL Department of Neuropathology, Institute of Psychiatry, The Maudsley HospitalLondon, S.E.5 The Derbyshire Royal InfirmaryDerby and National Institutes of HealthBerhesda, Maryland, U.S.A. Search for other works by this author on: Oxford Academic PubMed Google Scholar W. B. MATTHEWS, W. B. MATTHEWS Department of Neuropathology, Institute of Psychiatry, The Maudsley HospitalLondon, S.E.5 The Derbyshire Royal InfirmaryDerby and National Institutes of HealthBerhesda, Maryland, U.S.A. Search for other works by this author on: Oxford Academic PubMed Google Scholar D. L. STEVENS, D. L. STEVENS Department of Neuropathology, Institute of Psychiatry, The Maudsley HospitalLondon, S.E.5 The Derbyshire Royal InfirmaryDerby and National Institutes of HealthBerhesda, Maryland, U.S.A. Search for other works by this author on: Oxford Academic PubMed Google Scholar M. P. ALPERS, M. P. ALPERS Department of Neuropathology, Institute of Psychiatry, The Maudsley HospitalLondon, S.E.5 The Derbyshire Royal InfirmaryDerby and National Institutes of HealthBerhesda, Maryland, U.S.A. Search for other works by this author on: Oxford Academic PubMed Google Scholar D. M. ASHER, D. M. ASHER Department of Neuropathology, Institute of Psychiatry, The Maudsley HospitalLondon, S.E.5 The Derbyshire Royal InfirmaryDerby and National Institutes of HealthBerhesda, Maryland, U.S.A. Search for other works by this author on: Oxford Academic PubMed Google Scholar D. C. GAJDUSEK, D. C. GAJDUSEK Department of Neuropathology, Institute of Psychiatry, The Maudsley HospitalLondon, S.E.5 The Derbyshire Royal InfirmaryDerby and National Institutes of HealthBerhesda, Maryland, U.S.A. Search for other works by this author on: Oxford Academic PubMed Google Scholar C. J. GIBBS, JR. C. J. GIBBS, JR. Department of Neuropathology, Institute of Psychiatry, The Maudsley HospitalLondon, S.E.5 The Derbyshire Royal InfirmaryDerby and National Institutes of HealthBerhesda, Maryland, U.S.A. Search for other works by this author on: Oxford Academic PubMed Google Scholar Brain, Volume 92, Issue 4, March 1969, Pages 699–716, https://doi.org/10.1093/brain/92.4.699 Published: 01 March 1969 Article history Received: 03 July 1968 Published: 01 March 1969