set of tissues by currently available tests. PrPSc (the protease-resistant protein associated with prion disease) is neurotropic, so ultimately, it affects cells of the nervous system tissues. However, where and how PrPSc progresses through the body prior to its final assault on the nervous system is largely unclear, complicating the ability to locate and detect it.

The similarities between host PrPC (the protease-sensitive cellular protein) and PrPSc pose a fundamental problem. Since it is normal to find PrPC in healthy individuals, detection tests must differentiate between the two proteins. The strategy so far has been to mix the test material with the proteinase K (PK) enzyme, which digests normal prion protein but only a portion of the abnormal protein. Then, various techniques, described below, detect the residual PrPSc after digestion. Since this process inadvertently reduces the small amount of original PrPSc captured, this approach is inherently less sensitive than methods that do not rely on PK digestion.1

The fact that only small amounts of the infectious prion may be available for detection in accessible living tissues such as blood, urine, and cerebrospinal fluid (CSF) challenges the diagnostician to develop a sufficiently sensitive test. In addition, diagnostic tests must be of sufficient specificity to differentiate between normal and abnormal prion proteins and, for some purposes, to discriminate between one or more strains of PrPSc-a challenge resulting from basic deficiencies in understanding of prion strain diversity and the nature of strain variation.

This then introduces the ultimate objective of a prion detection test: find a single infectious unit while avoiding a falsely positive test result. Reaching this objective will be a complicated task, because a single infectious unit is a variable measure rather than a static one. For example, the size of a single infectious unit of prions injected intracerebrally would be different than the size of a single infectious unit of prions given parenterally, intravenously, or orally. The smallest amount of prions needed to cause an infection may also vary by the strain of prion involved, by the physical composition of aggregated prion molecules, by the type of source tissue, and by the genetic susceptibility of the host animal or person.

The quest for antemortem diagnostics will play a fundamental role in controlling the spread of TSEs, yet current tests are largely

1  

The degree to which PrPSc resists PK digestion depends on its strain. The limit of resistance to PK digestion may relate to the conformation of each strain (Safar et al., 1998). Some loss of PrPSc is also due to the test process itself.



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