Transmissible spongiform encephalopathies (TSEs) or prion diseases can be efficiently transmitted by blood. Significant progress has been made, in recent years, in the field of the TSEs’ pathognomonic marker (PrPTSE) detection in blood; however, a routine blood test for the diagnosis of prion diseases is yet unavailable. This delay in developing a PrPSc-based blood test that can be introduced into routine clinical practice indicates that the challenges and limitations that may affect the reliability and feasibility of detecting PrPSc using blood still remain. This perspective summarizes the potential challenges and highlights those that still need to be overcome to enable the development of a routine blood test not only for prion diseases but also for prion-like neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, which involve related mechanisms. Furthermore, this mini-review highlights that in order to be able to develop a successful routine blood test for prion diseases, it may be essential to overcome all of the potential limitations not only because they hinder the identification of PrPSc in different ways, but also because these limitations are present heterogeneously in infected subjects.
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