Cerebrospinal Fluid Total Prion Protein in the Spectrum of Prion Diseases

Abstract

Cerebrospinal fluid (CSF) total prion protein (t-PrP) is decreased in sporadic Creutzfeldt-Jakob disease (sCJD). However, data on the comparative signatures of t-PrP across the spectrum of prion diseases, longitudinal changes during disease progression, and levels in pre-clinical cases are scarce. T-PrP was quantified in neurological diseases (ND, n = 147) and in prion diseases from different aetiologies including sporadic (sCJD, n = 193), iatrogenic (iCJD, n = 12) and genetic (n = 209) forms. T-PrP was also measured in serial lumbar punctures obtained from sCJD cases at different symptomatic disease stages, and in asymptomatic prion protein gene (PRNP) mutation carriers. Compared to ND, t-PrP concentrations were significantly decreased in sCJD, iCJD and in genetic prion diseases associated with the three most common mutations E200K, V210I (associated with genetic CJD) and D178N-129M (associated with fatal familial insomnia). In contrast, t-PrP concentrations in P102L mutants (associated with the Gerstmann-Sträussler-Scheinker syndrome) remained unaltered. In serial lumbar punctures obtained at different disease stages of sCJD patients, t-PrP concentrations inversely correlated with disease progression. Decreased mean t-PrP values were detected in asymptomatic D178-129M mutant carriers, but not in E200K and P102L carriers. The presence of low CSF t-PrP is common to all types of prion diseases regardless of their aetiology albeit with mutation-specific exceptions in a minority of genetic cases. In some genetic prion disease, decreased levels are already detected at pre-clinical stages and diminish in parallel with disease progression. Our data indicate that CSF t-PrP concentrations may have a role as a pre-clinical or early symptomatic diagnostic biomarker in prion diseases as well as in the evaluation of therapeutic interventions.

Plasma total prion protein as a potential biomarker for neurodegenerative dementia: diagnostic accuracy in the spectrum of prion diseases

“…Another striking result is the dissociation between plasma t‐PrP and CSF t‐PrP in prion disease cases, where plasma t‐PrP is increased and CSF t‐PrP is reduced . This finding diverges from those obtained for other brain‐derived proteins such as tau, neuron‐specific enolase or S100B proteins among others, whose levels increase in both fluids upon brain damage.…”

“…It can be found in body fluids, such as cerebrospinal fluid (CSF), where several studies have reported that it is reduced in cases of sporadic Creutzfeldt‐Jakob disease (sCJD) , which is the most prevalent form of human prion disease. However, the diagnostic accuracy of CSF t‐PrP in the discrimination of prion diseases is limited and alternative CSF‐based biomarkers such as total‐tau, 14‐3‐3 and the real‐time quaking‐induced conversion (RT‐QuIC) are those mainly used for a sCJD diagnosis . Blood is another source of biomarkers containing significant amounts of PrP, particularly in the plasma fraction , but data regarding the levels of PrP in blood‐based fluids and their relationship with neurological disorders are still scarce and not conclusive.…”

Domain-specific quantification of prion protein in cerebrospinal fluid by targeted mass spectrometry

“…PrP is sufficiently abundant in CSF, at concentrations of tens or hundreds of nanograms per milliliter, to be readily quantified with enzyme-linked immunosorbent assay (ELISA). Studies using ELISA have reproducibly found that CSF PrP is decreased in the symptomatic phase of prion disease 3,[13][14][15][16] . Therefore, even though CSF PrP is brain-derived and exhibits good withinsubject test-retest reliability in individuals without prion disease 3 , it might be difficult to use this biomarker to read out the effect of a PrP-lowering drug in symptomatic individuals, because it is unclear whether to expect that such a drug should cause a further decrease in CSF PrP as a direct pharmacodynamic effect, or an increase in CSF PrP due to alleviation of the disease process.…”

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

“…Multicentric studies with the same samples and using larger cohorts might be required to face standardization issues. Similarly, developing protocols to standardize sample collection and handling will be of great importance as has been already demonstrated in the case of surrogate biomarkers [76].…”

“…Although it could apparently have limited utility in differential diagnosis with other neurodegenerative disorders, further studies using larger cohorts of CJD-affected patients concluded that, in combination with other surrogate biomarkers (i.e., tau and Aβ 42 ), total PrP levels are useful to distinguish them from patients suffering from Alzheimer's disease [74,75]. Apart from sCJD cases included in the previous reports, a recent study analyzed total PrP levels in CSF of iatrogenic CJD cases and several genetic prion diseases, showing also decreased levels in all tested cases except for the GSS associated with P102L mutation [76]. Furthermore, they observed that in sCJD patients at different stages and in the case of asymptomatic carriers of FFI-causing mutation, total PrP is reduced as disease progresses, making it a possible prognostic biomarker and an adequate parameter for evaluating future therapeutic interventions.…”