Phenotypic variability in human prion diseases.

National Creutzfeldt-Jakob Disease Surveillance Unit, Division of Pathology, University of Edinburgh, UK.
Neuropathology and Applied Neurobiology (Impact Factor: 4.97). 01/2006; 31(6):565-79. DOI: 10.1111/j.1365-2990.2005.00697.x
Source: PubMed

ABSTRACT Human prion diseases are rare neurodegenerative disorders that can occur as sporadic, familial or acquired disorders. Within each of these categories there is a wide range of phenotypic variation that is not encountered in other neurodegenerative disorders. The identification of the prion protein and its key role in the pathogenesis of this diverse group of diseases has allowed a fuller understanding of factors that influence disease phenotype. In particular, the naturally occurring polymorphism at codon 129 in the prion protein gene has a major influence on the disease phenotype in sporadic, familial and acquired prion diseases, although the underlying mechanisms remain unclear. Recent technical advances have improved our ability to study the isoforms of the abnormal prion protein in the brain and in other tissues. This has lead to the concept of molecular strain typing, in which different isoforms of the prion protein are proposed to correspond to individual strains of the transmissible agent, each with specific biological properties. In sporadic Creutzfeldt-Jakob disease there are at least six major combinations of codon 129 genotype and prion protein isotype, which appear to relate to distinctive clinical subgroups of this disease. However, these relationships are proving to be more complex than first considered, particularly in cases with more than a single prion protein isotype in the brain. Further work is required to clarify these relationships and to explain the mechanism of neuropathological targeting of specific brain regions, which accounts for the diversity of clinical features within human prion diseases.

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    • "Neuropathologic findings of sCJD are characterized by spongiform degeneration in the gray matter, gliosis with hypertrophic astrocytosis, neuropil rarefaction, neuron loss, and PrP deposition [1] [2] [3] [4] [5]. The histological pattern, progression, and distribution particularly in the cerebral cortex are highly characteristic [1] [2] [3] [4] [5]. In general, the cerebral cortex is the most severely affected region in sCJD pathology, and the severity tends to be associated with total disease duration [1] [2] [3]. "
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    ABSTRACT: In our pathologic observation of the cerebral cortex including the neocortex, hippocampus, and limbic cortex in 43 Japanese patients with MM1-type sporadic Creutzfeldt-Jakob disease, the earliest pathologic finding was spongiform change and next was gliosis. Subsequently, neuropil rarefaction appeared, followed by neuron loss. On the basis of these observations, we propose the following cortical pathologic staging: Stage I, spongiform change; Stage II, hypertrophic astrocytosis; Stage III, neuropil rarefaction; Stage IV, neuron loss; Stage V, status spongiosus; and Stage VI, large cavity formation. We also suggest a more simple staging classification: Stages I and II, mild; Stages III and IV, moderate; and Stages V and VI, severe involvement. Based on statistical analysis of the cases, strong correlation coefficients were obtained between the neocortical and limbic pathologic stage and both total disease duration and brain weight. We estimated that the first observation times of cortical hyperintensity on diffusion-weighted images of magnetic resonance imaging, myoclonus, and periodic sharp wave complexes on the electroencephalogram approximately correspond to the early phase of Stage II of the neocortex. The time to reach the akinetic mutism state approximately corresponds to the middle phase of Stage II of the neocortex. Therefore, we think that approximate clinical manifestations at death, total disease duration, and brain weight can be estimated according to the pathologic stage of the neocortex or limbic cortex. Panencephalopathic-type pathology appeared approximately 12months after disease onset, and this time approximately corresponds to the middle phase of Stage III of the neocortex.
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    • "pathological form of the prion protein ( protease-resistant prion protein, PrP res or scrapie prion protein, PrP sc ) and spongiform degeneration in the gray matter (Ironside et al., 2005). In addition, as for other neurodegenerative diseases, astrocytosis and microglial activation are present in both animal and human forms of prion diseases, which supports the occurrence of a local chronic inflammatory response (Perry et al., 2002). "
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    ABSTRACT: Cyclooxygenase (COX) catalyzes the first committed step in the synthesis of prostaglandins (PGs) and is the main target of nonsteroidal anti-inflammatory drugs (NSAIDs). The enzyme exists as constitutive (COX-1) and inducible (COX-2) isoforms, being the latter a major player in inflammation. In the brain, COX-2 expression has been associated with inflammatory and neurodegenerative processes of several human neurological diseases. Prion diseases, or transmissible spongiform encephalopathies, are a heterogeneous group of fatal neurodegenerative disorders, characterized by deposition of the protease-resistant prion protein, astrocytosis, and spongiform degeneration. In addition, an extensive microglial activation supports the occurrence of local chronic inflammatory response. In experimental prion diseases, COX-2 immunoreactivity was found specifically localized to microglial cells and increased with the progression of disease, along with the number of activated microglia. The induction of COX-2 was paralleled by a substantial raise in the brain homogenate PGE(2) levels. In these models, only few scattered COX-1-positive microglia-like cells were detected, suggesting that COX-2 is the major form in prion diseases. In line with the animal models, elevated levels of PGE(2) were found in the cerebrospinal fluid of subjects affected by sporadic, genetic, or variant CJD. In sporadic CJD patients, the most numerous group of patients examined, higher CSF levels of PGE(2) were associated with shorter survival. Although the mechanisms leading to microglial COX-2 expression as well as its potential implication in prion disease pathogenesis remain to be established, PGE(2) levels in the cerebrospinal fluid might represent an important index to predict survival and disease severity.
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