Abstract
The objective of the study was to develop a model for the diagnosis of prion diseases in live animals, using magnetic resonance imaging (MRI). Hamsters experimentally infected with the 263K strain of scrapie were imaged periodically during the course of prion infection. Changes in the brain, particularly the hippocampus, were observed during the first quarter of the incubation period. These changes included an increase in T2 relaxation time and apparent diffusion coefficient (ADC), indicative of an increase in the water content of tissues. These changes were apparent well before the appearance of clinical symptoms, and did not correlate with the typical histological changes characteristic of prion disease, (vacuolation, accumulation of PrP protein, gliosis) suggesting that the changes are caused by a progressive accumulation of fluid. This oedema may be a novel early marker of prion disease, and could play a role in pathogenesis.
Highlights
Transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of invariably fatal neurodegenerative diseases of both humans and animals caused, in whole or in part, by an abnormallyfolded form of the normal cellular protein PrP [1].The normal form of this protein, known as PrPC, undergoes a conformational change during which it acquires a significant amount of β-sheet [2,3], producing the pathological form, PrPSc, which is partially protease resistant and insoluble [2,4].Prion diseases exist in genetic, sporadic, and acquired forms, all of which are transmissible [5].The most common human prion disease is Creutzfeld-Jakob Disease (CJD), the variant form of which is likely acquired through ingestion of beef from Bovine Spongiform Encephalopathy (BSE) infected cattle [1,6,7]
The differences observed in pre-clinical MR images did not correlate with the typical histological hallmarks of prion disease, and occurred earlier in the incubation period, potentially identifying a new marker for brain pathology
The fluid content of brain tissue appeared to increase in the hippocampus early in disease progression, as evidenced by changes in T2 relaxation time and apparent diffusion coefficient observed by magnetic resonance imaging (MRI)
Summary
Transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of invariably fatal neurodegenerative diseases of both humans and animals caused, in whole or in part, by an abnormallyfolded form of the normal cellular protein PrP [1].The normal form of this protein, known as PrPC, undergoes a conformational change during which it acquires a significant amount of β-sheet [2,3], producing the pathological form, PrPSc, which is partially protease resistant and insoluble [2,4].Prion diseases exist in genetic, sporadic, and acquired forms, all of which are transmissible [5].The most common human prion disease is Creutzfeld-Jakob Disease (CJD), the variant form (vCJD) of which is likely acquired through ingestion of beef from Bovine Spongiform Encephalopathy (BSE) infected cattle [1,6,7]. Other prion diseases include scrapie of sheep and goats, and Chronic Wasting Disease (CWD) of deer and elk in North America. Rodent adapted prion strains, such as the 263K strain of scrapie in Syrian golden hamsters, are useful models due to the relatively short incubation period of 68-71 days following intracerebral infection [8,9,10]. Prion diseases are characterized by the deposition of PrPSc, the appearance of vacuoles, and gliosis in the brain [5]. Different strains can be distinguished by the distributions of these histological markers in a given host. The unequivocal diagnosis of most prion diseases requires the post-mortem collection of central nervous system tissue, either for histological examination or Western blot analysis
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