Challenges and Advances in Antemortem Diagnosis of Human Transmissible Spongiform Encephalopathies

Abstract

Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, arise from the structural conversion of the monomeric, cellular prion protein (PrP C ) into its multimeric scrapie form (PrP Sc ). These pathologies comprise a group of intractable, rapidly evolving neurodegenerative diseases. Currently, a definitive diagnosis of TSE relies on the detection of PrP Sc and/or the identification of pathognomonic histological features in brain tissue samples, which are usually obtained postmortem or, in rare cases, by brain biopsy (antemortem). Over the past two decades, several paraclinical tests for antemortem diagnosis have been developed to preclude the need for brain samples. Some of these alternative methods have been validated and can provide a probable diagnosis when combined with clinical evaluation. Paraclinical tests include in vitro cell-free conversion techniques, such as the real-time quakinginduced conversion (RT-QuIC), as well as immunoassays, electroencephalography (EEG), and brain bioimaging methods, such as magnetic resonance imaging (MRI), whose importance has increased over the years. PrP Sc is the main biomarker in TSEs, and the RT-QuIC assay stands out for its ability to detect PrP Sc in cerebrospinal fluid (CSF), olfactory mucosa, and dermatome skin samples with high sensitivity and specificity. Other biochemical biomarkers are the proteins 14-3-3, tau, neuronspecific enolase (NSE), astroglial protein S100B, α-synuclein, and neurofilament light chain protein (NFL), but they are not specific for TSEs. This paper reviews the techniques employed for definite diagnosis, as well as the clinical and paraclinical methods for possible and probable diagnosis, both those in use currently and those no longer employed. We also discuss current criteria, challenges, and perspectives for TSE diagnosis. An early and accurate diagnosis may allow earlier implementation of strategies to delay or stop disease progression.

Viral and Prion Infections Associated with Central Nervous System Syndromes in Brazil

“…World Health Organization criteria date from 2003. Therefore, they do not include analyses that have improved and developed the criteria after that date [ 247 ].…”

“…To classify as a probable or possible TSE, evaluation of symptoms is highly important, but is not sufficient in isolation. Paraclinical tests are essential for the classification of cases and the distinction of other treatable pathologies with similar symptoms [ 247 ]. Table 2 indicates the diagnostic criteria for sCJD classification according to the CDC [ 248 ].…”

“…In addition to its high sensitivity and specificity, the RT-QuIC assay has several advantages, not only for sCJD but also for other TSEs [ 247 ]. It is a relatively simple method based on the auto-propagating properties of PrP Sc .…”

Clinical Use of Improved Diagnostic Testing for Detection of Prion Disease

“…Other surrogate markers of neurodegeneration may be helpful in a diagnostic workup, but have varying sensitivities and specificities for prion disease [ 72 ], as listed in Table 2 . Neuron specific enolase (NSE), a marker of brain cell death, is also elevated in acute stroke.…”

Development of α-Synuclein Real-Time Quaking-Induced Conversion as a Diagnostic Method for α-Synucleinopathies

“…Detection of abnormal aggregated α-syn in CSF of DLB patients by the RT-QuIC assay was first reported by Fairfoul et al (2016) ; this was followed by multiple clinical studies. At present, diagnostic methods using skin ( Orru et al, 2017 ) or OM ( Orru et al, 2014 ; Bongianni et al, 2017 ), which includes CSF, have been reported ( Satoh et al, 2017 ; Ascari et al, 2020 ; Candelise et al, 2020 ).…”