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Neuropathology ArticleClinical and Neuropathological Investigations inCreutzfeldt-Jakob DiseaseTransmissible spongiform encephalopathies (TSEs),also known as prion diseases, are a group of rareand invariably fatal degenerative diseases of thecentral nervous system affecting humans as well as a numberof animal species. 1 Enormous public and scientificattention has focused on prion diseases, not only becauseof their unique biological properties, but also because oftheir impact on animal and public health, particularlywith the emergence of bovine spongiform encephalopathy(BSE) 2 and variant Creutzfeldt-Jakob disease (variantCJD) in the United Kingdom. 3 Unlike other forms of CJD,infectivity is readily detectable within lymphoid tissues invariant CJD, 4 raising concerns over the potential spread ofvariant CJD by iatrogenic means, particularly throughsurgical procedures and surgical instruments, as the infectiousagent shows an alarming resistance to conventionaldecontamination methods. More recently it has beenshown that variant CJD also appears to be transmissibleby blood transfusion, heightening concerns over secondaryhuman-to-human spread of the disease via contaminatedblood products. 5,6In humans, prion diseases occur in three main groups;they may occur sporadically, by autosomal dominantinheritance through mutations or insertions in the prionprotein gene (PRNP), or by secondary transmissionthrough either dietary or medical exposure to the infectiousagent. 7 Traditionally, human prion diseases are classifiedaccording to their major clinical features intoCreutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), fatal familial insomnia (FFI) andkuru (Table 1). All forms of prion disease share four neuropathologicalfeatures (spongiform vacuolation, neuronalloss, astrocytic and microglial proliferation and in certaincases the presence of amyloid plaques), which althoughcharacteristic of these disorders are not entirely specific. 8All prion diseases are associated with the conversion ofthe normal cellular host encoded prion protein, PrP C , to anabnormal disease-associated isoform, PrP SC .PrP SC is notonly a diagnostic marker of disease, but has been proposedas the sole or principal component of the transmissibleagent in prion disease. According to the ‘prion hypothesis’,PrP SC is derived from the normal cellular protein (PrP C ) bya post-translational mechanism, which appears to involvea conformational change. 9 This involves refolding of theprotein to a structure containing a high beta sheet content,which readily forms aggregates and is more resistant todenaturation by proteases than PrP C .Genetic and molecular aspects of sporadic CJDThe most common form of human prion disease is sporadicCJD, which accounts for around 85% of all humanprion diseases, with a world wide incidence of around 1-Table 1: Classification of human prion diseasesAetiologySporadicFamilialAcquiredDiseaseSporadic Creutzfeldt-Jakob DiseaseSporadic Fatal InsomniaFamilial CJDGerstmann-Sträussler-ScheinkerFatal Familial InsomniaKuru (human source)Iatrogenic CJD (human source)Variant CJD (bovine source)1.5 cases per million of the population per annum. Like allhuman prion diseases, much phenotypic heterogeneityexists within sporadic CJD in terms of clinical and pathologicalfeatures. 10 This heterogeneity has been linked withthe polymorphism found at codon 129 on PRNP whichencodes either methionine (M) or valine (V). 11 This polymorphismhas also been identified as an important riskfactor in sporadic CJD; most cases occur in individualswho are homozygous for methionine at codon 129, whopresent with the most ‘typical’ clinical and pathologicalfeatures. Cases of sporadic CJD in heterozygotes andvaline homozygotes are rarer and display more ‘atypical’phenotypes (Table 2). 12The physicochemical properties of PrP SC also play animportant role in influencing the disease phenotype insporadic CJD. Western blot analysis of the protease resistantcore of PrP SC , referred to as PrPres, has identified twokinds of heterogeneity within the brains of patients withCJD. Firstly, differences occur in the mobility of the proteaseresistant core, presumably relating to differentPrPres fragment sizes after proteinase K-mediated N-terminaltruncation, and secondly, variation occurs in therelative abundance of the three PrP glycoforms (diglycosylated,monoglycosylated and nonglycosylated).Following the classification of Parchi et al. 13 two distinctPrP SC types or PrPres isotypes, have been identified afterproteinase K digestion: one with a mobility on westernblot of around 21kDa named PrPres type 1, and the second,which is slightly smaller with a molecular weight ofaround 19kDa named PrPres type 2 (Figure 1). 13 This classificationsystem has been further subdivided to incorporatePrPres isotype combined with codon 129 PRNPgenotype (MM, MV, VV) resulting in six different sporadicCJD subtypes. 14 Examination of the clinical andpathological data from each of these subtypes shows thatalthough not all have a distinct phenotype, there doesappear to be a good correlation between clinical and neuropathologicalfeatures and disease subtype (Table 2).More recently, the observation of CJD patients with morethan one PrPres isotype within the brain has combined toincrease the heterogeneity and complexity observed insporadic CJD.The presence of distinct strains of the infectious agentin prion diseases has been established for some time, particularlyin relation to scrapie in sheep. However, the presenceof individual strains remains difficult to explainwithin the bounds of the prion hypothesis, which proposesthat all the information required for individual strainphenotypes is contained within the prion protein itself. 9In sporadic CJD, the different conformations of PrPres asdetermined by western blot analysis have been proposedto represent different biological profiles of the transmissibleagent, which may in turn relate to different biologicalstrains. Confirmation that these different molecular conformationsor isoforms of the prion protein do indeedcorrespond to distinct strains will require analysis of thebiological properties (such as incubation period and pat-Professor James Ironside is aNeuropathologist in Edinburghwho has been involved in theNational CJD Surveillance Unitsince 1990. In 1996, he and his colleaguesidentified variant CJD, thenew human prion disease which islinked to BSE. His current researchinterests include the tissue distributionof infectivity in all forms ofCJD, and the neuropathology ofpaediatric gliomas.Diane Ritchie started her career inprion diseases at the Institute forAnimal Health, NeuropathogenesisUnit, under the guidance ofProfessor Moira Bruce looking atexperimental models of scrapie.Currently she is studying at theNational CJD Surveillance Unitlooking at human prion diseaseswith Professor James Ironside,where she has refined the PET blottechnique for use on human tissue.Correspondence to:Ms Diane L Ritchie,National CJD Surveillance Unit,Western General Hospital,Edinburgh EH4 2XU, UK.Tel: 0131 537 1980Fax: 0131 537 3056Email: diane.ritchie@ed.ac.ukFigure 1: Western blot analysis of PrPres from the frontalcortex of two different sporadic CJD (s) patients, showing thetype 1 and type 2 mobility variants. The distinctive type 2Bpattern found in variant CJD (v) patients, with apredominance in the diglycosylated PrPres is also shown.20 I ACNR • VOLUME 5 NUMBER 6 • JANUARY/FEBRUARY 2006
Neuropathology ArticleTable 2: Clinical and pathological features of sporadic CJD subtypes (adapted from Parchi et al, Ann Neurol 1999) 14Sporadic CJD Subtype Mean disease duration (months) Clinical symptoms Patterns of PrP depositionMM1/MV1 3.9 Cortical visual impairment (41% of cases), Widespread and intense perivacuolar depositsrapidly progressive dementia, involvement around areas of confluent spongiformof the pyramidal and extrapyramidal systems, change with synaptic labellingMyoclonus.throughout the cerebral cortical layers.MM2 (cortical variant) 15.7 Progressive dementia. Intense perivacuolar labelling around areas ofconfluent spongiform change.MM2 (thalamic variant) 15.6 Ataxia and cognitive impairment with the PrP depositions less intense in this subtype;addition of insomnia.widespread synaptic positivity particularlytargeting the occipital cortex; cerebellumrelatively spared.MV2 17.1 Dementia at clinical onset (50% of cases) Intense labelling of kuru plaques,often with ataxia or extrapyramidal signs. most obvious in the cerebellum. Synapticpositivity present in the granular layer ofthe cerebellum.VV1 15.3 Progressive dementia. Weak and widespread synaptic labelling;cerebellum is relatively spared.VV2 6.5 Progressive ataxia with dementia developing Perineuronal positivity within the cerebralduring later stages.cortex and intense plaque like deposits in thebasal ganglia.2A2B2C3A3B3Cterns of neuropathology) after transmission tolaboratory mice. In variant CJD, which is recognisedas a distinct human prion strain closelyrelated to the BSE strain in cattle, 15 the biologicalprofile on western blot analysis is also distinctfrom other human prion diseases, with amobility much like that found in type 2 sporadicCJD cases, but with a unique glycoformratio in which there is a predominance of thedi-glycosylated band. 16 The PrPres isotype ofvariant CJD patients is referred to as type 2B todistinguish it from the type 2 found in sporadicCJD (Figure 1). The PrPres isotype of variantCJD cases resembles that of BSE in cattle and ina range of other species, which has helped confirmthat BSE was undoubtedly the source ofvariant CJD. 16Diagnosing human prion diseaseAlthough clinical criteria for the diagnosis ofhuman prion disease with a high degree of certaintyhave been agreed, 17 a definitive diagnosisrequires the examination of biopsy or postmortembrain material for the presence ofPrP SC . Immunohistochemical detection usingantibodies raised against the prion protein isinvaluable in the pathological diagnosis of2D3DFigure 2: Immunohistochemistry for the prion protein(PrP) in sporadic CJD subtypes. All sections areimmunolabelled with the KG9 anti-PrP antibody andcounterstained with Haematoxylin. (A) Frontal cortex in thesporadic CJD MM1 subtype showing intense perivacuolarpositivity around areas of confluent spongiform change.Original magnification x200. (B) Cerebellum in the sporadicCJD MV2 subtype showing intense positivity of kuruplaques in the granular layer. Original magnification x400.(C) Perineuronal labelling in the occipital cortex in thesporadic CJD VV2 subtype. Also shown is the widespreaddeposition of synaptic positivity. Original magnificationx400. (D) Faint synaptic labelling within the cerebral cortexin the sporadic CJD VV1. Original magnification x200.Figure 3: Detection of the prion protein (PrP) in peripheralorgans in variant CJD comparing the PET blot analysis (3F4anti-PrP antibody) and immunohistochemistry (KG9 anti-PrP antibody). (A) Immunohistochemistry and (B) PETblot analysis in the tonsil in variant CJD. (C)Immunohistochemistry and (D) PET blot analysis in adorsal root ganglion in variant CJD.ACNR • VOLUME 5 NUMBER 6 • JANUARY/FEBRUARY 2006 I 21
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