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Biomolecules
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Prion Disease Biomarkers: Recent Advances
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Prion Disease Biomarkers: Recent Advances

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Natural and Bio-inspired Molecules".

Deadline for manuscript submissions: closed (31 March 2020) | Viewed by 27453

Special Issue Editor

Dr. Franc Llorens

E-Mail Website
Guest Editor
Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
Interests: prion diseases; rapidly progressive dementias and neurodegeneratve diseases; development and implemention of new biomarker platforms for disease diagnosis; prognosis and disease monitoring; molecular neuropathology of human neurodegenarative diseases

Special Issue Information

Dear Colleagues,

Prion diseases or transmissible spongiform encephalopathies (TSEs) are a family of rare and fatal progressive neurodegenerative disorders caused by prions, which are the abnormal and pathogenic forms of the cellular prion protein (PrP), affecting humans and animals.

In humans, prion diseases are classified according to their etiology in sporadic (sporadic Creutzfeldt–Jakob disease—the most prevalent form accounting for approximately 85% of all prion disease cases), genetic (genetic Creutzfeld–Jakob disease, fatal familial insomnia, and Gerstmann–Sträussler–Scheinker syndrome), and acquired (iatrogenic Creutzfeldt–Jakob disease, variant Creutzfeldt–Jakob disease, and kuru) forms.

Prion disease can exhibit a variety of clinical manifestations that make their differential diagnosis challenging. Indeed, definite diagnosis is only possible through neuropathological examination of the pathological isoform of the prion protein (PrPSc) in the central nervous system through a biopsy or autopsy. However, implementation in clinical settings over the last few decades of fluid and neuroimaging biomarkers has generated a set of assays displaying high accuracies in the discrimination of prion diseases. Some of these assays are already included in the diagnostic criteria for these conditions.

Despite great advances in the diagnosis of prion disease-symptomatic individuals, early diagnosis is still challenging due to the absence of a long pre-symptomatic phase, in contrast to what occurs in other neurodegenerative diseases, such as Alzheimer’s disease. Less is known about the role of current biomarkers in disease prognosis in terms of predicting the severity and rapidity of the disease. Similarly, the use of prion biomarkers as potential tools for the evaluation of the efficacy of disease-modifying therapies in therapeutic trials is still in its infancy.

In this Special Issue of Biomolecules called “Prion Disease Biomarkers: Recent Advances”, we would like to explore recent aspects in the field of prion biomarker research, especially in new aspects related to disease diagnosis and prognosis, as well as the potential contribution of prion biomarkers in the design and interpretation of eventual clinical trials.

Dr. Franc Llorens
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • prion diseases
  • neurodegeneration
  • biomarkers
  • cerebrospinal fluid
  • blood
  • neuroimaging
  • diagnosis
  • prognosis
  • disease monitoring

Published Papers (8 papers)

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Research

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21 pages, 7979 KiB  
Article
MicroRNA Alterations in a Tg501 Mouse Model of Prion Disease
by Janne M. Toivonen, David Sanz-Rubio, Óscar López-Pérez, Alba Marín-Moreno, Rosa Bolea, Rosario Osta, Juan J. Badiola, Pilar Zaragoza, Juan-Carlos Espinosa, Juan-Maria Torres and Inmaculada Martín-Burriel
Biomolecules 2020, 10(6), 908; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10060908 - 15 Jun 2020
Cited by 5 | Viewed by 2644
Abstract
MicroRNAs (miRNAs) may contribute to the development and pathology of many neurodegenerative diseases, including prion diseases. They are also promising biomarker candidates due to their stability in body fluids. We investigated miRNA alterations in a Tg501 mouse model of prion diseases that expresses [...] Read more.
MicroRNAs (miRNAs) may contribute to the development and pathology of many neurodegenerative diseases, including prion diseases. They are also promising biomarker candidates due to their stability in body fluids. We investigated miRNA alterations in a Tg501 mouse model of prion diseases that expresses a transgene encoding the goat prion protein (PRNP). Tg501 mice intracranially inoculated with mouse-adapted goat scrapie were compared with age-matched, mock inoculated controls in preclinical and clinical stages. Small RNA sequencing from the cervical spinal cord indicated that miR-223-3p, miR-151-3p, and miR-144-5p were dysregulated in scrapie-inoculated animals before the onset of symptoms. In clinical-stage animals, 23 significant miRNA alterations were found. These miRNAs were predicted to modify the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways including prion disease, extracellular matrix interactions, glutaminergic synapse, axon guidance, and transforming growth factor-beta signaling. MicroRNAs miR-146a-5p (up in cervical spinal cord) and miR-342-3p (down in cervical spinal cord, cerebellum and plasma), both indicated in neurodegenerative diseases earlier, were verified by quantitative real-time polymerase chain reaction (qRT-PCR). Minimal changes observed before the disease onset suggests that most miRNA alterations observed here are driven by advanced prion-associated pathology, possibly limiting their use as diagnostic markers. However, the results encourage further mechanistic studies on miRNA-regulated pathways involved in these neurodegenerative conditions. Full article
(This article belongs to the Special Issue Prion Disease Biomarkers: Recent Advances)
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21 pages, 9290 KiB  
Article
BAMBI and CHGA in Prion Diseases: Neuropathological Assessment and Potential Role as Disease Biomarkers
by Óscar López-Pérez, Marcos Bernal-Martín, Adelaida Hernaiz, Franc Llorens, Marina Betancor, Alicia Otero, Janne Markus Toivonen, Pilar Zaragoza, Inga Zerr, Juan José Badiola, Rosa Bolea and Inmaculada Martín-Burriel
Biomolecules 2020, 10(5), 706; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10050706 - 02 May 2020
Cited by 6 | Viewed by 2502
Abstract
Prion diseases affect both animals and humans. Research in the natural animal model of the disease could help in the understanding of neuropathological mechanisms and in the development of biomarkers for human pathologies. For this purpose, we studied the expression of 10 genes [...] Read more.
Prion diseases affect both animals and humans. Research in the natural animal model of the disease could help in the understanding of neuropathological mechanisms and in the development of biomarkers for human pathologies. For this purpose, we studied the expression of 10 genes involved in prion propagation in vitro in the central nervous system of scrapie-infected sheep. Dysregulated genes (BAMBI and CHGA) were further analysed in a transgenic murine model (Tg338) of scrapie, and their protein distribution was determined using immunohistochemistry and Western blot. Their potential as biomarkers was finally assessed using enzyme-linked immunosorbent assay (ELISA) in cerebrospinal fluid (CSF) of scrapie sheep and Creutzfeldt-Jakob disease (CJD) patients. Protein BAMBI was upregulated in highly affected brain areas and CHGA was overexpressed along the brain in both models. Moreover, BAMBI and CHGA immunostaining scores strongly correlated with spongiosis and microgliosis in mice. Finally, levels of BAMBI were significantly higher in the CSF of clinical sheep and CJD patients. In addition to their potential as biomarkers, our work confirms the role of BAMBI and CHGA in prion neuropathology in vivo, but besides prion replication, they seem to be involved in the characteristic neuroinflammatory response associated to prion infection. Full article
(This article belongs to the Special Issue Prion Disease Biomarkers: Recent Advances)
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12 pages, 1842 KiB  
Article
CSF Ubiquitin Levels Are Higher in Alzheimer’s Disease than in Frontotemporal Dementia and Reflect the Molecular Subtype in Prion Disease
by Samir Abu-Rumeileh, Patrick Oeckl, Simone Baiardi, Steffen Halbgebauer, Petra Steinacker, Sabina Capellari, Markus Otto and Piero Parchi
Biomolecules 2020, 10(4), 497; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10040497 - 25 Mar 2020
Cited by 7 | Viewed by 3130
Abstract
Disturbances in the ubiquitin-proteasome system seem to play a role in neurodegenerative dementias (NDs). Previous studies documented an increase of cerebrospinal fluid (CSF) free monoubiquitin in Alzheimer’s disease (AD) and Creutzfeldt–Jakob disease (CJD). However, to date, no study explored this biomarker across the [...] Read more.
Disturbances in the ubiquitin-proteasome system seem to play a role in neurodegenerative dementias (NDs). Previous studies documented an increase of cerebrospinal fluid (CSF) free monoubiquitin in Alzheimer’s disease (AD) and Creutzfeldt–Jakob disease (CJD). However, to date, no study explored this biomarker across the heterogeneous spectrum of prion disease. Using a liquid chromatography−multiple reaction monitoring mass spectrometry, we investigated CSF free monoubiquitin in controls (n = 28) and in cases with prion disease (n = 84), AD (n = 38), and frontotemporal dementia (FTD) (n = 30). Furthermore, in CJD subtypes, we evaluated by immunohistochemistry (IHC) the relative extent of brain ubiquitin deposits. Prion disease and, to a lesser extent, AD subjects showed increased levels of CSF free monoubiquitin, whereas FTD cases had median protein values similar to controls. The biomarker showed a good to optimal accuracy in the differential diagnosis between NDs and, most interestingly, between AD and FTD. After stratification, according to molecular subtypes, sporadic CJD VV2 demonstrated significantly higher levels of CSF ubiquitin and more numerous brain ubiquitin deposits at IHC in comparison to the typical and most prevalent MM(V)1 subtype. Moreover, CSF ubiquitin correlated with biomarkers of neurodegeneration and astrogliosis in NDs, and was associated with disease stage but not with survival in prion disease. The differential increase of CSF free monoubiquitin in prion disease subtypes and AD may reflect common, though disease and time-specific, phenomena related to neurodegeneration, such as neuritic damage, dysfunctional proteostasis, and neuroinflammation. Full article
(This article belongs to the Special Issue Prion Disease Biomarkers: Recent Advances)
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13 pages, 463 KiB  
Article
Diagnostic Accuracy of Prion Disease Biomarkers in Iatrogenic Creutzfeldt-Jakob Disease
by Franc Llorens, Anna Villar-Piqué, Peter Hermann, Matthias Schmitz, Olga Calero, Christiane Stehmann, Shannon Sarros, Fabio Moda, Isidre Ferrer, Anna Poleggi, Maurizio Pocchiari, Marcella Catania, Sigrid Klotz, Carl O’Regan, Francesca Brett, Josephine Heffernan, Anna Ladogana, Steven J. Collins, Miguel Calero, Gabor G. Kovacs and Inga Zerradd Show full author list remove Hide full author list
Biomolecules 2020, 10(2), 290; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10020290 - 12 Feb 2020
Cited by 11 | Viewed by 3875
Abstract
Human prion diseases are classified into sporadic, genetic, and acquired forms. Within this last group, iatrogenic Creutzfeldt–Jakob disease (iCJD) is caused by human-to-human transmission through surgical and medical procedures. After reaching an incidence peak in the 1990s, it is believed that the iCJD [...] Read more.
Human prion diseases are classified into sporadic, genetic, and acquired forms. Within this last group, iatrogenic Creutzfeldt–Jakob disease (iCJD) is caused by human-to-human transmission through surgical and medical procedures. After reaching an incidence peak in the 1990s, it is believed that the iCJD historical period is probably coming to an end, thanks to lessons learnt from past infection sources that promoted new prion prevention and decontamination protocols. At this point, we sought to characterise the biomarker profile of iCJD and compare it to that of sporadic CJD (sCJD) for determining the value of available diagnostic tools in promptly recognising iCJD cases. To that end, we collected 23 iCJD samples from seven national CJD surveillance centres and analysed the electroencephalogram and neuroimaging data together with a panel of seven CSF biomarkers: 14-3-3, total tau, phosphorylated/total tau ratio, alpha-synuclein, neurofilament light, YKL-40, and real-time quaking induced conversion of prion protein. Using the cut-off values established for sCJD, we found the sensitivities of these biomarkers for iCJD to be similar to those described for sCJD. Given the limited relevant information on this issue to date, the present study validates the use of current sCJD biomarkers for the diagnosis of future iCJD cases. Full article
(This article belongs to the Special Issue Prion Disease Biomarkers: Recent Advances)
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11 pages, 1863 KiB  
Article
Characterization of the Prion Protein Binding Properties of Antisense Oligonucleotides
by Andrew G. Reidenbach, Eric Vallabh Minikel, Hien T. Zhao, Stacy G. Guzman, Alison J. Leed, Michael F. Mesleh, Holly B. Kordasiewicz, Stuart L. Schreiber and Sonia M. Vallabh
Biomolecules 2020, 10(1), 1; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10010001 - 18 Dec 2019
Cited by 11 | Viewed by 3588
Abstract
Antisense oligonucleotides (ASOs) designed to lower prion protein (PrP) expression in the brain through RNase H1-mediated degradation of PrP RNA are in development as prion disease therapeutics. ASOs were previously reported to sequence-independently interact with PrP and inhibit prion accumulation in cell culture, [...] Read more.
Antisense oligonucleotides (ASOs) designed to lower prion protein (PrP) expression in the brain through RNase H1-mediated degradation of PrP RNA are in development as prion disease therapeutics. ASOs were previously reported to sequence-independently interact with PrP and inhibit prion accumulation in cell culture, yet in vivo studies using a new generation of ASOs found that only PrP-lowering sequences were effective at extending survival. Cerebrospinal fluid (CSF) PrP has been proposed as a pharmacodynamic biomarker for trials of such ASOs, but is only interpretable if PrP lowering is indeed the relevant mechanism of action in vivo and if measurement of PrP is unconfounded by any PrP–ASO interaction. Here, we examine the PrP-binding and antiprion properties of ASOs in vitro and in cell culture. Binding parameters determined by isothermal titration calorimetry were similar across all ASOs tested, indicating that ASOs of various chemistries bind full-length recombinant PrP with low- to mid-nanomolar affinity in a sequence-independent manner. Nuclear magnetic resonance, dynamic light scattering, and visual inspection of ASO–PrP mixtures suggested, however, that this interaction is characterized by the formation of large aggregates, a conclusion further supported by the salt dependence of the affinity measured by isothermal titration calorimetry. Sequence-independent inhibition of prion accumulation in cell culture was observed. The inefficacy of non-PrP-lowering ASOs against prion disease in vivo may be because their apparent activity in vitro is an artifact of aggregation, or because the concentration of ASOs in relevant compartments within the central nervous system (CNS) quickly drops below the effective concentration for sequence-independent antiprion activity after bolus dosing into CSF. Measurements of PrP concentration in human CSF were not impacted by the addition of ASO. These findings support the further development of PrP-lowering ASOs and of CSF PrP as a pharmacodynamic biomarker. Full article
(This article belongs to the Special Issue Prion Disease Biomarkers: Recent Advances)
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10 pages, 987 KiB  
Article
Evaluation of Human Cerebrospinal Fluid Malate Dehydrogenase 1 as a Marker in Genetic Prion Disease Patients
by Inga Zerr, Anna Villar-Piqué, Vanda Edit Schmitz, Anna Poleggi, Maurizio Pocchiari, Raquel Sánchez-Valle, Miguel Calero, Olga Calero, Inês Baldeiras, Isabel Santana, Gabor G. Kovacs, Franc Llorens and Matthias Schmitz
Biomolecules 2019, 9(12), 800; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9120800 - 28 Nov 2019
Cited by 7 | Viewed by 2874
Abstract
The exploration of accurate diagnostic markers for differential diagnosis of neurodegenerative diseases is an ongoing topic. A previous study on cerebrospinal fluid (CSF)-mitochondrial malate dehydrogenase 1 (MDH1) in sporadic Creutzfeldt–Jakob disease (sCJD) patients revealed a highly significant upregulation of MDH1. Here, we measured [...] Read more.
The exploration of accurate diagnostic markers for differential diagnosis of neurodegenerative diseases is an ongoing topic. A previous study on cerebrospinal fluid (CSF)-mitochondrial malate dehydrogenase 1 (MDH1) in sporadic Creutzfeldt–Jakob disease (sCJD) patients revealed a highly significant upregulation of MDH1. Here, we measured the CSF levels of MDH1 via enzyme-linked immunosorbent assay in a cohort of rare genetic prion disease cases, such as genetic CJD (gCJD) cases, exhibiting the E200K, V210I, P102L (Gerstmann–Sträussler–Scheinker syndrome (GSS)), or D178N (fatal familial insomnia (FFI)) mutations in the PRNP. Interestingly, we observed enhanced levels of CSF-MDH1 in all genetic prion disease patients compared to neurological controls (without neurodegeneration). While E200K and V210I carriers showed highest levels of MDH1 with diagnostic discrimination from controls of 0.87 and 0.85 area under the curve (AUC), FFI and GSS patients exhibited only moderately higher CSF-MDH1 levels than controls. An impact of the PRNP codon 129 methionine/valine (MV) genotype on the amount of MDH1 could be excluded. A correlation study of MDH1 levels with other neurodegenerative marker proteins revealed a significant positive correlation between CSF-MDH1 concentration with total tau (tau) but not with 14-3-3 in E200K, as well as in V210I patients. In conclusion, our study indicated the potential use of MDH1 as marker for gCJD patients which may complement the current panel of diagnostic biomarkers. Full article
(This article belongs to the Special Issue Prion Disease Biomarkers: Recent Advances)
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Review

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44 pages, 437 KiB  
Review
Detection of Pathognomonic Biomarker PrPSc and the Contribution of Cell Free-Amplification Techniques to the Diagnosis of Prion Diseases
by Hasier Eraña, Jorge M. Charco, Ezequiel González-Miranda, Sandra García-Martínez, Rafael López-Moreno, Miguel A. Pérez-Castro, Carlos M. Díaz-Domínguez, Adrián García-Salvador and Joaquín Castilla
Biomolecules 2020, 10(3), 469; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10030469 - 19 Mar 2020
Cited by 9 | Viewed by 3806
Abstract
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 [...] Read more.
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 differential 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 different 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. Full article
(This article belongs to the Special Issue Prion Disease Biomarkers: Recent Advances)
14 pages, 311 KiB  
Review
PMCA Applications for Prion Detection in Peripheral Tissues of Patients with Variant Creutzfeldt-Jakob Disease
by Giorgio Giaccone and Fabio Moda
Biomolecules 2020, 10(3), 405; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10030405 - 05 Mar 2020
Cited by 14 | Viewed by 3966
Abstract
Prion diseases are neurodegenerative and invariably fatal conditions that affect humans and animals. In particular, Creutzfeldt-Jakob disease (CJD) and bovine spongiform encephalopathy (BSE) are paradigmatic forms of human and animal prion diseases, respectively. Human exposure to BSE through contaminated food caused the appearance [...] Read more.
Prion diseases are neurodegenerative and invariably fatal conditions that affect humans and animals. In particular, Creutzfeldt-Jakob disease (CJD) and bovine spongiform encephalopathy (BSE) are paradigmatic forms of human and animal prion diseases, respectively. Human exposure to BSE through contaminated food caused the appearance of the new variant form of CJD (vCJD). These diseases are caused by an abnormal prion protein named PrPSc (or prion), which accumulates in the brain and leads to the onset of the disease. Their definite diagnosis can be formulated only at post-mortem after biochemical and neuropathological identification of PrPSc. Thanks to the advent of an innovative technique named protein misfolding cyclic amplification (PMCA), traces of PrPSc, undetectable with the standard diagnostic techniques, were found in peripheral tissues of patients with vCJD, even at preclinical stages. The technology is currently being used in specialized laboratories and can be exploited for helping physicians in formulating an early and definite diagnosis of vCJD using peripheral tissues. However, this assay is currently unable to detect prions associated with the sporadic CJD (sCJD) forms, which are more frequent than vCJD. This review will focus on the most recent advances and applications of PMCA in the field of vCJD and other human prion disease diagnosis. Full article
(This article belongs to the Special Issue Prion Disease Biomarkers: Recent Advances)
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