Abstract:
Transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of invariably fatal neurodegenerative diseases of both humans and animals, thought to be caused by the abnormally folded prion protein PrPSc. Prion disease research continues to be faced by a number of difficult challenges. First, the unequivocal diagnosis of most prion diseases currently requires the post-mortem collection of central nervous system tissue, either for histological examination or Western blot analysis; second, a viable treatment for clinical stage disease has not yet been identified; third, the exact details of disease pathogenesis have not been elucidated; and fourth, the normal function of PrPC is not definitively known.
The primary objective of the studies presented here was to diagnose prion disease in live animals, using Magnetic Resonance Imaging (MRI). Increases in T2 relaxation time and apparent diffusion coefficient (ADC) were observed very early following the infection of Syrian golden hamsters with the 263K strain of scrapie. These changes were evident well before the appearance of either clinical symptoms or the typical histological changes characteristic of prion disease, suggesting that they are the result of the progressive accumulation of fluid, and that this may constitute a novel early marker of prion disease pathogenesis. Following the establishment of this model system, a secondary objective was composed: to test the viability of a potential treatment (pentosan polysulphate) using a number of different treatment regimens. It was determined that pentosan polysulphate (PPS) was ineffective as a treatment unless it was administered intra-cerebrally very early in infection, although it was shown to slow the appearance of the histological hallmarks of prion disease. In response to the results of these studies, a potential model was proposed, relating PrP, aquaporin-4 (AQP4) regulation, and oedema. Although speculative, this model may have implications for both normal PrPC function and disease pathogenesis.
