Detection of Pathognomonic Biomarker PrPSc and the Contribution of Cell Free-Amplification Techniques to the Diagnosis of Prion Diseases

Transmissible spongiform encephalopathies or prion diseases are rapidly progressive
neurodegenerative diseases, the clinical manifestation of which can resemble other promptly evolving
neurological maladies. Therefore, the unequivocal ante-mortem diagnosis is highly challenging and
was only possible by histopathological and immunohistochemical analysis of the brain at necropsy.
Although surrogate biomarkers of neurological damage have become invaluable to complement
clinical data and provide more accurate diagnostics at early stages, other neurodegenerative diseases
show similar alterations hindering the di erential diagnosis. To solve that, the detection of the
pathognomonic biomarker of disease, PrPSc, the aberrantly folded isoform of the prion protein, could
be used. However, the amounts in easily accessible tissues or body fluids at pre-clinical or early
clinical stages are extremely low for the standard detection methods. The solution comes from the
recent development of in vitro prion propagation techniques, such as Protein Misfolding Cyclic
Amplification (PMCA) and Real Time-Quaking Induced Conversion (RT-QuIC), which have been
already applied to detect minute amounts of PrPSc in di erent matrixes and make early diagnosis of
prion diseases feasible in a near future. Herein, the most relevant tissues and body fluids in which
PrPSc has been detected in animals and humans are being reviewed, especially those in which cell-free
prion propagation systems have been used with diagnostic purposes.