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

Abstract

2020) Neuropathology and Applied Neurobiology 46, 240-254 Plasma total prion protein as a potential biomarker for neurodegenerative dementia: diagnostic accuracy in the spectrum of prion diseases Aims: In the search for blood-based biomarkers of neurodegenerative diseases, we characterized the concentration of total prion protein (t-PrP) in the plasma of neurodegenerative dementias. We aimed to assess its accuracy in this differential diagnostic context. Methods: Plasma t-PrP was measured in 520 individuals including healthy controls (HC) and patients diagnosed with neurological disease control (ND), Alzheimer's disease (AD), sporadic Creutzfeldt-Jakob disease (sCJD), frontotemporal dementia (FTD), Lewy body dementia (LBD) and vascular dementia (VaD). Additionally, t-PrP was quantified in genetic prion diseases and iatrogenic CJD. The accuracy of t-PrP discriminating the diagnostic groups was evaluated and correlated with demographic, genetic and clinical data in prion diseases. Markers of blood-brain barrier impairment were investigated in sCJD brains. Results:Compared to HC and ND, elevated plasma t-PrP concentrations were detected in sCJD, followed by FTD, AD, VaD and LBD. In sCJD, t-PrP was associated neither with age nor sex, but with codon 129 PRNP genotype. Plasma t-PrP concentrations correlated with cerebrospinal fluid (CSF) markers of neuro-axonal damage, but not with CSF t-PrP. In genetic prion diseases, plasma t-PrP was elevated in all type of mutations investigated. In sCJD brain tissue, extravasation of immunoglobulin G and the presence of swollen astrocytic end-feet around the vessels suggested leakage of blood-brain barrier as a potential source of increased plasma t-PrP. Conclusions: Plasma t-PrP is elevated in prion diseases regardless of aetiology. This pilot study opens the possibility to consider plasma t-PrP as a promising blood-based biomarker in the diagnostic of prion disease.

Biomarkers and diagnostic guidelines for sporadic Creutzfeldt-Jakob disease

“…Interestingly, PrP was reported to be to be decreased in the CSF of sCJD cases 54,55 while it was increased in plasma. 84 This dissociation has not been clarified, yet.…”

Structure, Function, and Regulation of the Blood-Brain Barrier Tight Junction in Central Nervous System Disorders

“…Additionally, AD is demarcated by neurofibrillary tangles that are comprised of hyperphosphorylated intraneuronal deposits of the microtubule-associated protein tau ( Braak and Del Trecidi, 2015 ). A number of studies have shown increased extravasation of plasma proteins in AD brains, suggesting dysfunctional BBB properties ( Paul et al, 2007 ; Ryu and McLarnon, 2009 ; Narayan et al, 2015 ; Llorens et al, 2019 ). Several postmortem studies in patients with AD have shown a significant decrease in TJ proteins claudin-5, occludin, and ZO-1 in cerebral blood vessels exhibiting cerebral amyloid angiopathy ( Carrano et al, 2011 , 2012 ; Keaney et al, 2015 ).…”

Protein Aggregation Landscape in Neurodegenerative Diseases: Clinical Relevance and Future Applications

“…For instance, atypical parkinsonism, characterized by motor symptoms derived from au misfolding and aggregation, have been accurately differentiated from synucleinopathies according to real-time quaking-induced conversion results [234]. Along with kinetic analyses, improvements in antibody-mediated detection of specific conformation are paving the way for the usage of a combination ratio of aggregation-related and neuronal damage proteins as diagnostic biomarkers [242][243][244]. On the other side, anti-amyloidogenic compounds are being studied as potential therapeutics [245][246][247].…”