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.

  • Source
    [Show abstract] [Hide abstract]
    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.
    Journal of the neurological sciences 04/2014; 341(1-2). DOI:10.1016/j.jns.2014.04.011 · 2.26 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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.
    International Review of Neurobiology 02/2007; 82:265-75. DOI:10.1016/S0074-7742(07)82014-9 · 2.46 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare neurodegenerative disorder in humans included in the group of Transmissible Spongiform Encephalopathies or prion diseases. The vast majority of sCJD cases are molecularly classified according to the abnormal prion protein (PrPSc) conformations along with polymorphism of codon 129 of the PRNP gene. Recently, a novel human disease, termed "protease-sensitive prionopathy", has been described. This disease shows a distinct clinical and neuropathological phenotype and it is associated to an abnormal prion protein more sensitive to protease digestion. We report the case of a 75-year-old-man who developed a clinical course and presented pathologic lesions compatible with sporadic Creutzfeldt-Jakob disease, and biochemical findings reminiscent of "protease-sensitive prionopathy". Neuropathological examinations revealed spongiform change mainly affecting the cerebral cortex, putamen/globus pallidus and thalamus, accompanied by mild astrocytosis and microgliosis, with slight involvement of the cerebellum. Confluent vacuoles were absent. Diffuse synaptic PrP deposits in these regions were largely removed following proteinase treatment. PrP deposition, as revealed with 3F4 and 1E4 antibodies, was markedly sensitive to pre-treatment with proteinase K. Molecular analysis of PrPSc showed an abnormal prion protein more sensitive to proteinase K digestion, with a five-band pattern of 28, 24, 21, 19, and 16 kDa, and three aglycosylated isoforms of 19, 16 and 6 kDa. This PrPSc was estimated to be 80% susceptible to digestion while the pathogenic prion protein associated with classical forms of sporadic Creutzfeldt-Jakob disease were only 2% (type VV2) and 23% (type MM1) susceptible. No mutations in the PRNP gene were found and genotype for codon 129 was heterozygous methionine/valine. A novel form of human disease with abnormal prion protein sensitive to protease and MV at codon 129 was described. Although clinical signs were compatible with sporadic Creutzfeldt-Jakob disease, the molecular subtype with the abnormal prion protein isoforms showing enhanced protease sensitivity was reminiscent of the "protease-sensitive prionopathy". It remains to be established whether the differences found between the latter and this case are due to the polymorphism at codon 129. Different degrees of proteinase K susceptibility were easily determined with the chemical polymer detection system which could help to detect proteinase-susceptible pathologic prion protein in diseases other than the classical ones.
    BMC Neurology 10/2010; 10:99. DOI:10.1186/1471-2377-10-99 · 2.49 Impact Factor