Originally Posted on Nature Reviews | 1 October 2004
Prion diseases and prion diseases diagnosis are among the most intriguing topic for infectious diseases and are associated with unconventional proteinaceous infectious agents known as prions. Prions seem to lack nucleic acid and propagate by transmission of misfolded proteins. The nature of prions and their unique mode of transmission present challenges for early prion diseases diagnosis.
In this article, state-of-the-art prion diagnostic techniques, together with the new strategies that are being used to develop sensitive, early and non-invasive diagnoses for these diseases are reviewed.
Prion diseases, which are also called transmissible spongiform encephalopathies (TSEs), comprise a group of fatal infectious neurodegenerative diseases that include Creutzfeldt–Jakob disease (CJD), kuru, Gerstmann–Sträussler–Sheinker syndrome (GSS) and fatal familial insomnia (FFI) in humans, and scrapie, bovine spongiform encephalopathy (BSE) and chronic wasting disease (CWD) in animals.These diseases are characterized by brain vacuolation, ASTROGLIOSIS, neuronal APOPTOSIS and accumulation of the misfolded prion protein in the central nervous system.
In animals, the most common prion disease is scrapie, but the most infamous and dangerous disease is the recently discovered BSE, which affects cattle and is known worldwide by the lay term ‘mad cow disease.’ In humans, the most common TSE is CJD, which occurs worldwide with an incidence of 0.5–1.5 new cases per one million people each year.
Three different forms of CJD have traditionally been recognized: sporadic (sCJD; ~85% of cases), familial (fCJD; ~10%), and IATROGENIC (iCJD; ~5%). However, in 1996, a new variant form of CJD (vCJD) emerged in the United Kingdom,which has been associated with consumption of meat infected with BSE.In contrast with typical cases of sCJD, vCJD affects young patients (the average age of patients is 27 years), and is a relatively long illness (14 months compared with 4.5 months for sCJD).
Owing to insufficient information about the incubation time and the levels of exposure to contaminated cattle food products, it is impossible to make well-founded predictions about the potential future incidence of vCJD. In animals, there is no evidence for inherited forms of the disease and most cases seem to be acquired by horizontal or vertical transmission.
Although TSEs are neurodegenerative disorders, in some forms of the disease prions replicate and accumulate in lymphoid tissues markedly earlier than in the central nervous system. It seems that the orally ingested infectious agent is absorbed through the intestine into the blood, which transports it to lymphoid organs where the prions undergo a first round of replication and accumulation before being transported to the brain by the peripheral nerves. This pathway has been proposed on the basis of infectivity studies of different organs at various stages of the incubation period.
Recently, studies using brain perfusion and capillary depletion techniques in animals injected with purified PrPSc have suggested that prions can gain access to the brain directly through the blood–brain barrier. Regardless of the route by which the infectious agent enters the brain, it seems clear that prions can be associated with several peripheral tissues and biological fluids.