scholarly journals Laminar Distribution of the Pathological Changes in Sporadic and Variant Creutzfeldt-Jakob Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-7
Author(s):  
R. A. Armstrong
Keyword(s):  
Cerebral Cortex ◽  
Prion Diseases ◽  
Neuronal Loss ◽  
Pathological Changes ◽  
Spongiform Change ◽  
Protein Deposits ◽  
Laminar Distribution ◽  
Jakob Disease ◽  
Cortical Regions ◽  
The Brain

The laminar distributions of the pathological changes in the cerebral cortex were compared in the prion diseases sporadic Creutzfeldt-Jakob disease (sCJD) and variant CJD (vCJD). First, in some cortical regions, the vacuolation (“spongiform change”) was more generally distributed across the cortex in sCJD. Second, there was greater neuronal loss in the upper cortex in vCJD and in the lower cortex in sCJD. Third, the “diffuse” and “florid” prion protein () deposits were more frequently distributed in the upper cortex in vCJD and the “synaptic” deposits in the lower cortex in sCJD. Fourth, there was a significant gliosis mainly affecting the lower cortex of both disorders. The data suggest that the pattern of cortical degeneration is different in sCJD and vCJD which may reflect differences in aetiology and the subsequent spread of prion pathology within the brain.

Human Prion Diseases

2018 ◽  
pp. 159-171
Author(s):  
James W. Ironside
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Prion Diseases ◽  
Neuronal Loss ◽  
Human Prion Disease ◽  
Clinical Genetic ◽  
Jakob Disease ◽  
Biochemical Approach ◽  
Protein Isoform ◽  
The Brain

Human prion diseases include idiopathic, genetic, and acquired disorders. Heterogeneous clinicopathologic features make diagnosis challenging. Accurate diagnosis requires a combined clinical, neuropathologic, genetic, and biochemical approach. Neuropathologic assessment is performed following autopsy in most cases. The brain is sampled and studied by tinctorial stains and immunohistochemistry for disease-associated form of the prion protein. Unfixed frozen brain tissue is retained for Western blot analysis of protease-resistant prion protein isoform and for DNA extraction to sequence the prion protein gene. Assessment of spongiform change, gliosis neuronal loss, and accumulation of disease-associated prion protein in the brain can help to determine major categories of human prion disease. Additional clinical, genetic, and biochemical data allow diagnosis and subclassification into disease subtypes, particularly in sporadic Creutzfeldt–Jakob disease. Neuropathology continues to play a role in the recognition and understanding of the expanding spectrum of human prion disease and identification of disease variants that may emerge in the future.

Human Prion Diseases

2013 ◽  
pp. 149-160
Author(s):  
James W. Ironside ◽  
Matthew P. Frosch ◽  
Bernardino Ghetti
Keyword(s):  
Prion Diseases ◽  
Neuronal Loss ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Pituitary Hormone ◽  
Human Pituitary ◽  
Spongiform Encephalopathies ◽  
Jakob Disease ◽  
Prnp Codon ◽  
Codon 129

This chapter describes and illustrates the neuropathology of prion diseases, also known as transmissible spongiform encephalopathies. These diseases are characterized pathologically by varying combinations of spongiform change, neuronal loss, reactive gliosis, and prion protein (PrP) deposition. The morphologic pattern depends on the etiology of the disease and the genotype of the patient. Different clinicopathological phenotypes of sporadic Creutzfeldt-Jakob disease (CJD) have been described depending on the PRNP codon 129 genotype and the PrP isotype. A novel form known as variably protease-sensitive prionopathy has been recently identified. Familial prion diseases include familial CJD, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia. Over 40 different PRNP mutations have been identified. Acquired prion diseases include Kuru; iatrogenic CJD, particularly in recipients of contaminated human pituitary hormone, and variant CJD, which seems closely related to bovine spongiform encephalopathy.

scholarly journals Unilateral Creutzfeldt-Jakob Disease Presenting as Rapidly Progressive Aphasia

1994 ◽  
Vol 21 (4) ◽  
pp. 350-352 ◽  
Author(s):  
Andrew Kirk ◽  
L.C. Ang
Keyword(s):  
Left Hemisphere ◽  
Right Hemisphere ◽  
Molecular Layer ◽  
Neuronal Loss ◽  
Occipital Cortex ◽  
Spongiform Change ◽  
History Of ◽  
Jakob Disease ◽  
The Right ◽  
Ct And Mri

Abstract:A 64-year-old man presented with a three day history of progressive Broca’s aphasia, followed within 3 weeks by exclusively right-sided myoclonus, rigidity, and dystonia. Within 4 weeks he was globally aphasie. He died within 7 weeks of onset. In the final week, rigidity and myoclonus became bilateral. CT and MRI were normal. SPECT showed diminished perfusion of the left hemisphere. EEG showed periodic discharges on the left. At autopsy, there were marked cortical spongiform change, neuronal loss, and gliosis throughout the left hemisphere and in the right occipital cortex. Elsewhere in the right hemisphere, spongiform change was non-existent to minimal. There was moderate spongiform change in the molecular layer of the cerebellar cortex, much more marked on the left. Clinical and pathological unilateral cerebral predominance extended to the ipsilateral cerebellum. Creutzfeldt-Jakob disease is an important consideration in patients with rapidly progressive unilateral cerebral signs associated with a movement disorder.

scholarly journals Prion diseases: fatal familial insomnia

2021 ◽  
Vol 11 (9) ◽  
pp. 29-36
Author(s):  
Barbara Madoń ◽  
Eryk Mikos ◽  
Justyna Nowaczek ◽  
Martyna Wasyluk ◽  
Natalia Wilczek
Keyword(s):  
Nervous System ◽  
Molecular Mechanisms ◽  
Autosomal Dominant ◽  
Prion Diseases ◽  
Neuronal Loss ◽  
Preventive Treatment ◽  
Fatal Familial Insomnia ◽  
Average Survival Time ◽  
Average Survival ◽  
The Brain

Introduction. Fatal familial insomnia (FFI) is one of the transmissible spongiform encephathalopathies characterized by neuronal loss, sleep impairment, subsequent non-specific disturbances of autonomic nervous system (e.g. tachycardia) and endocrine dysfunctions. It is fatal autosomal dominant prion disease, which is extremaly rare- FFI affects only about one person per milion annually. The aim of this study is to review the literature and systematize knowledge about fatal familial insomnia.Brief description of the state of knowledge. The causative agent of this disease is a misfolded version of the physiological prion protein called PrP(Sc) in the brain.  Major vulnerable regions in FFI are mediodorsal and anterior ventral nuclei of the thalamus.  Average  survival time after the onset of symptoms is 18 months. Hence molecular mechanisms involved in pathogenesis are poorly understood, the disease is incureable yet. However, there are a number of therapeutic options currently under investigation, e.g. immunotherapy or doxycycline usage.Conclusions. Subsequent researches are essential to improve understending of fatal familial insomnia. The prime issue is to develop functioning therapeutic or preventive treatment. While some of presented terapeutic approches appers promising, all of them require profoud research.

scholarly journals From Prion Diseases to Prion-Like Propagation Mechanisms of Neurodegenerative Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Isabelle Acquatella-Tran Van Ba ◽  
Thibaut Imberdis ◽  
Véronique Perrier
Keyword(s):  
Neurodegenerative Disorders ◽  
Small Rnas ◽  
Prion Diseases ◽  
Cellular Prion Protein ◽  
Spongiform Encephalopathy ◽  
Wasting Disease ◽  
Original Works ◽  
Jakob Disease ◽  
The Brain ◽  
Prion Hypothesis

Prion diseases are fatal neurodegenerative sporadic, inherited, or acquired disorders. In humans, Creutzfeldt-Jakob disease is the most studied prion disease. In animals, the most frequent prion diseases are scrapie in sheep and goat, bovine spongiform encephalopathy in cattle, and the emerging chronic wasting disease in wild and captive deer in North America. The hallmark of prion diseases is the deposition in the brain of PrPSc, an abnormalβ-sheet-rich form of the cellular prion protein (PrPC) (Prusiner 1982). According to the prion hypothesis, PrPSccan trigger the autocatalytic conversion of PrPCinto PrPSc, presumably in the presence of cofactors (lipids and small RNAs) that have been recently identified. In this review, we will come back to the original works that led to the discovery of prions and to the protein-only hypothesis proposed by Dr. Prusiner. We will then describe the recent reports on mammalian synthetic prions and recombinant prions that strongly support the protein-only hypothesis. The new concept of “deformed templating” regarding a new mechanism of PrPScformation and replication will be exposed. The review will end with a chapter on the prion-like propagation of other neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease and tauopathies.

scholarly journals Oral administration of repurposed drug targeting Cyp46A1 increases survival times of prion infected mice

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Tahir Ali ◽  
Samia Hannaoui ◽  
Satish Nemani ◽  
Waqas Tahir ◽  
Irina Zemlyankina ◽  
...  
Keyword(s):  
Oral Administration ◽  
Prion Diseases ◽  
Neuronal Cells ◽  
Cellular Prion Protein ◽  
Disease Stage ◽  
Survival Times ◽  
Valuable Treatment ◽  
Advanced Disease Stage ◽  
Jakob Disease ◽  
The Brain

AbstractPrion diseases are fatal, infectious, and incurable neurodegenerative disorders caused by misfolding of the cellular prion protein (PrPC) into the infectious isoform (PrPSc). In humans, there are sporadic, genetic and infectious etiologies, with sporadic Creutzfeldt-Jakob disease (sCJD) being the most common form. Currently, no treatment is available for prion diseases. Cellular cholesterol is known to impact prion conversion, which in turn results in an accumulation of cholesterol in prion-infected neurons. The major elimination of brain cholesterol is achieved by the brain specific enzyme, cholesterol 24-hydroxylase (CYP46A1). Cyp46A1 converts cholesterol into 24(S)-hydroxycholesterol, a membrane-permeable molecule that exits the brain. We have demonstrated for the first time that Cyp46A1 levels are reduced in the brains of prion-infected mice at advanced disease stage, in prion-infected neuronal cells and in post-mortem brains of sCJD patients. We have employed the Cyp46A1 activator efavirenz (EFV) for treatment of prion-infected neuronal cells and mice. EFV is an FDA approved anti-HIV medication effectively crossing the blood brain barrier and has been used for decades to chronically treat HIV patients. EFV significantly mitigated PrPSc propagation in prion-infected cells while preserving physiological PrPC and lipid raft integrity. Notably, oral administration of EFV treatment chronically at very low dosage starting weeks to months after intracerebral prion inoculation of mice significantly prolonged the lifespan of animals. In summary, our results suggest that Cyp46A1 as a novel therapeutic target and that its activation through repurposing the anti-retroviral medication EFV might be valuable treatment approach for prion diseases.

scholarly journals Mechanisms of prion-induced neurodegeneration

2016 ◽  
Vol 18 ◽  
Author(s):  
Paula Saá ◽  
David A. Harris ◽  
Larisa Cervenakova
Keyword(s):  
Neurodegenerative Disorders ◽  
Protein Misfolding ◽  
Prion Diseases ◽  
Neuronal Loss ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Therapeutic Approaches ◽  
Spongiform Encephalopathies ◽  
Membrane Bound ◽  
The Brain

Transmissible spongiform encephalopathies (TSEs), or prion diseases, are fatal neurodegenerative disorders characterised by long incubation period, short clinical duration, and transmissibility to susceptible species. Neuronal loss, spongiform changes, gliosis and the accumulation in the brain of the misfolded version of a membrane-bound cellular prion protein (PrPC), termed PrPTSE, are diagnostic markers of these diseases. Compelling evidence links protein misfolding and its accumulation with neurodegenerative changes. Accordingly, several mechanisms of prion-mediated neurotoxicity have been proposed. In this paper, we provide an overview of the recent knowledge on the mechanisms of neuropathogenesis, the neurotoxic PrP species and the possible therapeutic approaches to treat these devastating disorders.

Prion disease

2012 ◽  
pp. 351-361
Author(s):  
John Collinge
Keyword(s):  
Diagnostic Criteria ◽  
Prion Disease ◽  
Prion Diseases ◽  
Case Reports ◽  
Neuronal Loss ◽  
Dietary Exposure ◽  
Spongiform Encephalopathy ◽  
Spongiform Encephalopathies ◽  
Jakob Disease ◽  
Classical Triad

The human prion diseases, also known as the subacute spongiform encephalopathies, have been traditionally classified into Creutzfeldt–Jakob disease (CJD), Gerstmann–Sträussler syndrome (GSS) (also known as Gerstmann–Sträussler–Scheinker disease), and kuru. Although rare, affecting about 1–2 per million worldwide per annum, remarkable attention has been recently focused on these diseases. This is because of the unique biology of the transmissible agent or prion, and also because bovine spongiform encephalopathy (BSE), an epidemic bovine prion disease, appears to have transmitted to humans as variant CJD (vCJD), opening the possibility of a significant threat to public health through dietary exposure to infected tissues. The transmissibility of the human diseases was demonstrated with the transmission, by intracerebral inoculation with brain homogenates into chimpanzees, of first kuru and then CJD in 1966 and 1968, respectively. Transmission of GSS followed in 1981. The prototypic prion disease is scrapie, a naturally occurring disease of sheep and goats, which has been recognized in Europe for over 200 years and which is present in the sheep flocks of many countries. Scrapie was demonstrated to be transmissible by inoculation in 1936 and the recognition that kuru, and then CJD, resembled scrapie in its histopathological appearances led to the suggestion that these diseases may also be transmissible. Kuru reached epidemic proportions amongst the Fore linguistic group in the Eastern Highlands of Papua New Guinea and was transmitted by ritual cannibalism. Since the cessation of cannibalism in the 1950s the disease has declined but a few cases still occur as a result of the long incubation periods in this condition, which may exceed 50 years. The term Creutzfeldt–Jakob disease was introduced by Spielmeyer in 1922 bringing together the case reports published by Creutzfeldt and Jakob. Several of these cases would not meet modern diagnostic criteria for CJD and indeed it was not until the demonstration of transmissibility allowed diagnostic criteria to be reassessed and refined that a clear diagnostic entity developed. All these diseases share common histopathological features; the classical triad of spongiform vacuolation (affecting any part of the cerebral grey matter), astrocytic proliferation, and neuronal loss, may be accompanied by the deposition of amyloid plaques.

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