The use of non-prion biomarkers for the diagnosis of Transmissible Spongiform Encephalopathies in the live animal

Abstract

-Scrapie and bovine spongiform encephalopathy (BSE) are major global concerns and the emergence of variant Creutzfeldt-Jakob disease (vCJD) has caused turmoil for blood transfusion services and hospitals worldwide. Recent reports of iatrogenic CJD (iCJD) cases following blood transfusions from Transmissible Spongiform Encephalopathies (TSE)-infected donors have fuelled this concern. Major diagnostic tests for BSE and scrapie are conducted post-mortem from animals in late stages of the disease. Although the lymphoreticular system is involved in the earlier pathogenesis of some forms of sheep scrapie and vCJD, which presents great opportunity for diagnostic development, other TSE diseases (some strains of scrapie, sporadic CJD (sCJD) and bovine BSE) do not present such a diagnostic opportunity. Thus, there is an urgent need for premortem tests that differentiate between healthy and diseased individuals at early stages of illness, in accessible samples such as blood and urine using less invasive procedures. This review reports on the current state of progress in the development and use of prion and non-prion biomarkers in the diagnosis of TSE diseases. Some of these efforts have concentrated on improving the sensitivity of PrP Sc detection to allow in vivo diagnosis at low abundances of PrP Sc whilst others have sought to identify non-prion protein biomarkers of TSE disease, many of which are still at early stages of development. In this review we comment upon the limitations of prion based tests and review current research on the development of tests for TSE that rely on non-prion disease markers in body fluids that may allow preclinical disease diagnosis.

Gene Expression Profiling and Association with Prion-Related Lesions in the Medulla Oblongata of Symptomatic Natural Scrapie Animals

“…In previous studies, the ApoE protein has been proposed as a biomarker for prion diseases [48], [49], [50], [51] in addition to its role in the Alzheimer's disease pathway [52], [53]. Several studies have also reported the involvement of many members of the apolipoprotein gene family ( ApoA1 , ApoA4 , ApoC1 , ApoC2 , ApoC3 and ApoD ) in transmissible spongiform encephalopathies [26], [30], [54], [55].…”

Proteomics-based Development of Biomarkers for Prion Diseases

“…However, definite diagnoses of prion diseases are limited because these analyses require neuropathological confirmation by brain biopsy or post-mortem examination. Several protein markers, including 14-3-3 protein [1,2], Tau [3], astrocytic protein S-100 [4], apolipoprotein E [5], neuron-specific enolase [6], and cystatin C [7] have been reported in the cerebrospinal fluid of patients showing clinical symptoms of CJD. The assay for 14-3-3 protein that has been used in the laboratory diagnosis of CJD has high false-positive rates.…”

Progress and limits of TSE diagnostic tools

“…The problem is particularly acute for blood transfusion, insofar as it is now well established that vCJD can be transmitted by blood. Considerable effort has been devoted to the search for alternative markers enabling earlier diagnosis of TSE (for a review see Parveen et al [55]). …”

“…However, none of these markers has proved usable as a basis for a sufficiently sensitive and specific test allowing early preclinical diagnosis. Metabolic markers, such as fatty acidbinding proteins, interferon γ, prostaglandin E2, C-reactive protein, interleukin 6, cystatin C, and corticosteroids, have also been studied, but with no more success (for a review see Parveen et al [55]). …”