Association of #Blood and #CSF #Tau Level and Other #Biomarkers With #Survival Time in Sporadic #CJD (JAMA Neurol., abstract)

[Source: JAMA Neurology, full page: (LINK). Abstract, edited.]

Original Investigation / May 6, 2019

Association of Blood and Cerebrospinal Fluid Tau Level and Other Biomarkers With Survival Time in Sporadic Creutzfeldt-Jakob Disease

Adam M. Staffaroni, PhD 1; Abigail O. Kramer, MS 1,2; Megan Casey, BS1; et al Huicong Kang, MD 1,3; Julio C. Rojas, MD, PhD 1; Christina D. Orrú, PhD 4; Byron Caughey, PhD 4; I. Elaine Allen, PhD 5; Joel H. Kramer, PsyD 1; Howard J. Rosen, MD 1; Kaj Blennow, MD, PhD 6,7; Henrik Zetterberg, MD, PhD 6,7,8,9; Michael D. Geschwind, MD, PhD 1

Author Affiliations: 1 UCSF Memory and Aging Center, Department of Neurology, University of California, San Francisco; 2 Department of Psychology, Palo Alto University, Palo Alto, California; 3 Department of Neurology, Tongji Hospital affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 4 Rocky Mountain Laboratories, National Institute of Allergy and Infectious Disease, National Institutes of Health, Hamilton, Montana; 5 Department of Biostatistics and Epidemiology, University of California, San Francisco; 6 Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 7 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden; 8 Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom; 9 UK Dementia Research Institute, University College London, London, United Kingdom

JAMA Neurol. 2019;76(8):969-977. doi:10.1001/jamaneurol.2019.1071

 

Key Points

  • Question  – Can fluid biomarkers improve prediction of survival time in sporadic Creutzfeldt-Jakob disease (sCJD) above and beyond demographic and genetic biomarkers?
  • Findings  – In this longitudinal cohort study including 188 participants with probable or definite sCJD and codon 129 genotyping, in addition to polymorphisms of prion protein gene codon 129 and baseline functional status, several cerebrospinal fluid–based and blood-based biomarkers were associated with survival in patients with sCJD. Total tau concentrations in the blood and cerebrospinal fluid appear to be the most promising.
  • Meaning  – This study provides evidence that blood-based biomarkers can be used to predict survival in patients with sCJD, potentially improving clinical care and our ability to power treatment trials.

 

Abstract

Importance  

Fluid biomarkers that can predict survival time in sporadic Creutzfeldt-Jakob disease (sCJD) will be critical for clinical care and for treatment trials.

Objective  

To assess whether plasma and cerebrospinal fluid (CSF) biomarkers are associated with survival time in patients with sCJD.

Design, Setting, and Participants  

In this longitudinal cohort study, data from 193 patients with probable or definite sCJD who had codon 129 genotyping referred to a tertiary national referral service in the United States were collected from March 2004 to January 2018. Participants were evaluated until death or censored at the time of statistical analysis (range, 0.03-38.3 months). We fitted Cox proportional hazard models with time to event as the outcome. Fluid biomarkers were log-transformed, and models were run with and without nonfluid biomarkers of survival. Five patients were excluded because life-extending measures were performed.

Main Outcomes and Measures  

Biomarkers of survival included sex, age, codon 129 genotype, Barthel Index, Medical Research Council Prion Disease Rating Scale, 8 CSF biomarkers (total tau [t-tau] level, phosphorylated tau [p-tau] level, t-tau:p-tau ratio, neurofilament light [NfL] level, β-amyloid 42 level, neuron-specific enolase level, 14-3-3 test result, and real-time quaking-induced conversion test), and 3 plasma biomarkers (t-tau level, NfL level, and glial fibrillary acidic protein level).

Results  

Of the 188 included participants, 103 (54.8%) were male, and the mean (SD) age was 63.8 (9.2) years. Plasma t-tau levels (hazard ratio, 5.8; 95% CI, 2.3-14.8; P < .001) and CSF t-tau levels (hazard ratio, 1.6; 95% CI, 1.2-2.1; P < .001) were significantly associated with survival after controlling for codon 129 genotype and Barthel Index, which are also associated with survival time. Plasma and CSF t-tau levels were correlated (r = 0.74; 95% CI, 0.50-0.90; P < .001). Other fluid biomarkers associated with survival included plasma NfL levels, CSF NfL levels, t-tau:p-tau ratio, 14-3-3 test result, and neuron-specific enolase levels. In a restricted subset of 23 patients with data for all significant biomarkers, the hazard ratio for plasma t-tau level was more than 40% larger than any other biomarkers (hazard ratio, 3.4; 95% CI, 1.8-6.4).

Conclusions and Relevance  

Cerebrospinal fluid and plasma tau levels, along with several other fluid biomarkers, were significantly associated with survival time in patients with sCJD. The correlation between CSF and plasma t-tau levels and the association of plasma t-tau level with survival time suggest that plasma t-tau level may be a minimally invasive fluid biomarker in sCJD that could improve clinical trial stratification and guide clinical care.

Keywords: CJD; Prions; Neurology.

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#Clinical #Variability in P102L Gerstmann‐Sträussler‐Scheinker Syndrome [#GSS] (Ann Neurol., abstract)

[Source: Annals of Neurology, full page: (LINK). Abstract, edited.]

Clinical Variability in P102L Gerstmann‐Sträussler‐Scheinker Syndrome

Adam Tesar MD,  Radoslav Matej MD, PhD,  Jaromir Kukal PhD,  Silvie Johanidesova MSc,  Irena Rektorova MD, PhD,  Martin Vyhnalek MD, PhD,  Jiri Keller MD, PhD,  Ilona Eliasova MD, PhD,  Eva Parobkova MSc, Magdalena Smetakova MSc,  Zuzana Musova PhD, Robert Rusina MD, PhD

First published: 09 August 2019 / DOI:  https://doi.org/10.1002/ana.25579

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/ana.25579.

 

Abstract

Gerstmann‐Sträussler‐Scheinker syndrome (GSS) with the P102L mutation is a rare genetic prion disease caused by a pathogenic mutation at codon 102 in the prion protein gene. Cluster analysis encompassing data from seven Czech patients and 87 published cases suggests the existence of four clinical phenotypes (“typical GSS,” “GSS with areflexia and paresthesia,” “pure dementia GSS,” and “Creutzfeldt‐Jakob disease‐like GSS”); GSS may be more common than previously estimated. In making a clinical diagnosis or progression estimates of GSS, MRI, and RT‐QuIC may be helpful, but the results should be evaluated with respect to the overall clinical context.

This article is protected by copyright. All rights reserved.

Keywords: Prions; Prion’s diseases; CJD; GSS.

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Early existence and #biochemical #evolution characterise acutely synaptotoxic #PrPSc (PLoS Pathog., abstract)

[Source: PLoS Pathogens, full page: (LINK). Abstract, edited.]

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Early existence and biochemical evolution characterise acutely synaptotoxic PrPSc

Simote Totauhelotu Foliaki, Victoria Lewis, Abu Mohammed Taufiqual Islam, Laura Jane Ellett, Matteo Senesi, David Isaac Finkelstein, Blaine Roberts, Victoria A. Lawson, Paul Anthony Adlard, Steven John Collins

Published: April 10, 2019 / DOI: https://doi.org/10.1371/journal.ppat.1007712 / This is an uncorrected proof.

 

Abstract

Although considerable evidence supports that misfolded prion protein (PrPSc) is the principal component of “prions”, underpinning both transmissibility and neurotoxicity, clear consensus around a number of fundamental aspects of pathogenesis has not been achieved, including the time of appearance of neurotoxic species during disease evolution. Utilizing a recently reported electrophysiology paradigm, we assessed the acute synaptotoxicity of ex vivo PrPSc prepared as crude homogenates from brains of M1000 infected wild-type mice (cM1000) harvested at time-points representing 30%, 50%, 70% and 100% of the terminal stage of disease (TSD). Acute synaptotoxicity was assessed by measuring the capacity of cM1000 to impair hippocampal CA1 region long-term potentiation (LTP) and post-tetanic potentiation (PTP) in explant slices. Of particular note, cM1000 from 30% of the TSD was able to cause significant impairment of LTP and PTP, with the induced failure of LTP increasing over subsequent time-points while the capacity of cM1000 to induce PTP failure appeared maximal even at this early stage of disease progression. Evidence that the synaptotoxicity directly related to PrP species was demonstrated by the significant rescue of LTP dysfunction at each time-point through immuno-depletion of >50% of total PrP species from cM1000 preparations. Moreover, similar to our previous observations at the terminal stage of M1000 prion disease, size fractionation chromatography revealed that capacity for acute synpatotoxicity correlated with predominance of oligomeric PrP species in infected brains across all time points, with the profile appearing maximised by 50% of the TSD. Using enhanced sensitivity western blotting, modestly proteinase K (PK)-resistant PrPSc was detectable at very low levels in cM1000 at 30% of the TSD, becoming robustly detectable by 70% of the TSD at which time substantial levels of highly PK-resistant PrPSc was also evident. Further illustrating the biochemical evolution of acutely synaptotoxic species the synaptotoxicity of cM1000 from 30%, 50% and 70% of the TSD, but not at 100% TSD, was abolished by digestion of immuno-captured PrP species with mild PK treatment (5μg/ml for an hour at 37°C), demonstrating that the predominant synaptotoxic PrPScspecies up to and including 70% of the TSD were proteinase-sensitive. Overall, these findings in combination with our previous assessments of transmitting prions support that synaptotoxic and infectious M1000 PrPSc species co-exist from at least 30% of the TSD, simultaneously increasing thereafter, albeit with eventual plateauing of transmitting conformers.

 

Author summary

Although evidence clearly supports that misfolded prion protein (PrPSc) is the principal component of “prions”, underpinning both transmissibility and neurotoxicity, consensus is lacking around the time of appearance and biochemical profile of neurotoxic species during disease evolution. Employing an electrophysiology model, measuring the capacity of brain homogenates derived from across the disease time-course to impair CA1 region long-term potentiation (LTP) and post-tetanic potentiation (PTP) in hippocampal slices, we observed that synaptotoxic species were present from 30% of the terminal stage of disease (TSD). Evidence that synaptotoxicity directly related to PrP species was demonstrated by significant rescue of LTP dysfunction at each time-point through immuno-depleting >~50% of total PrP species from cM1000 preparations. Moreover, size fractionation chromatography revealed that acute synpatotoxicity correlated with predominance of oligomeric PrP species in infected brains across all time points, while additional characterisation of cM1000 demonstrated that the predominant synaptotoxic PrPSc species up to and including 70% of the TSD were quite proteinase-sensitive. These findings in combination with our previous assessments of transmitting prions support that synaptotoxic and infectious M1000 PrPSc species co-exist from at least 30% of the TSD, simultaneously increasing thereafter, with biochemical transformation of synaptotoxic conformers continuing until late in disease.

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Citation: Foliaki ST, Lewis V, Islam AMT, Ellett LJ, Senesi M, Finkelstein DI, et al. (2019) Early existence and biochemical evolution characterise acutely synaptotoxic PrPSc. PLoS Pathog 15(4): e1007712. https://doi.org/10.1371/journal.ppat.1007712

Editor: David Westaway, University of Alberta, CANADA

Received: October 7, 2018; Accepted: March 18, 2019; Published: April 10, 2019

Copyright: © 2019 Foliaki et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: The author(s) received no specific funding for this work

Competing interests: The authors have declared that no competing interests exist.

Keywords: Prions; Neurology.

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#Prion protein quantification in #human #CSF as a #tool for prion disease #drug development (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Prion protein quantification in human cerebrospinal fluid as a tool for prion disease drug development

Sonia M. Vallabh, Chloe K. Nobuhara, Franc Llorens, Inga Zerr, Piero Parchi, Sabina Capellari, Eric Kuhn, Jacob Klickstein, Jiri G. Safar, Flavia C. Nery, Kathryn J. Swoboda, Michael D. Geschwind, Henrik Zetterberg, Steven E. Arnold, Eric Vallabh Minikel, and Stuart L. Schreiber

PNAS published ahead of print April 1, 2019 / DOI: https://doi.org/10.1073/pnas.1901947116

Contributed by Stuart L. Schreiber, February 26, 2019 (sent for review February 7, 2019; reviewed by Emiliano Biasini and Sina Ghaemmaghami)

 

Significance

Human prion disease is a rapidly fatal and incurable neurodegenerative disease. Reduction of prion protein in the brain is a well-supported therapeutic hypothesis, and antisense oligonucleotides with this mechanism of action are currently in development. To facilitate clinical testing of prion protein-lowering drugs in prion disease, we show that with proper sample handling, brain prion protein levels can be monitored in cerebrospinal fluid, using existing tools, and exhibit suitable short-term stability for drug-dependent decreases to be reliably measured. Cerebrospinal fluid prion protein levels thus may usefully serve as a pharmacodynamic biomarker. This biomarker may open new paths for informative clinical trials in presymptomatic individuals who harbor high-risk mutations for genetic prion disease.

 

Abstract

Reduction of native prion protein (PrP) levels in the brain is an attractive strategy for the treatment or prevention of human prion disease. Clinical development of any PrP-reducing therapeutic will require an appropriate pharmacodynamic biomarker: a practical and robust method for quantifying PrP, and reliably demonstrating its reduction in the central nervous system (CNS) of a living patient. Here we evaluate the potential of ELISA-based quantification of human PrP in human cerebrospinal fluid (CSF) to serve as a biomarker for PrP-reducing therapeutics. We show that CSF PrP is highly sensitive to plastic adsorption during handling and storage, but its loss can be minimized by the addition of detergent. We find that blood contamination does not affect CSF PrP levels, and that CSF PrP and hemoglobin are uncorrelated, together suggesting that CSF PrP is CNS derived, supporting its relevance for monitoring the tissue of interest and in keeping with high PrP abundance in brain relative to blood. In a cohort with controlled sample handling, CSF PrP exhibits good within-subject test–retest reliability (mean coefficient of variation, 13% in samples collected 8–11 wk apart), a sufficiently stable baseline to allow therapeutically meaningful reductions in brain PrP to be readily detected in CSF. Together, these findings supply a method for monitoring the effect of a PrP-reducing drug in the CNS, and will facilitate development of prion disease therapeutics with this mechanism of action.

prion protein – cerebrospinal fluid – biomarker – human prion disease – Creutzfeldt-Jakob disease

 

Footnotes

1 To whom correspondence may be addressed. Email: svallabh@broadinstitute.org, eminikel@broadinstitute.org, or stuart_schreiber@harvard.edu.

Author contributions: S.M.V., H.Z., S.E.A., E.V.M., and S.L.S. designed research; S.M.V., C.K.N., J.K., and E.V.M. performed research; F.L., I.Z., P.P., S.C., E.K., J.G.S., F.C.N., K.J.S., M.D.G., H.Z., and S.E.A. contributed new reagents/analytic tools; E.K. advised on experimental design; F.C.N., K.J.S., and M.D.G. contributed to experimental design; S.M.V. and E.V.M. analyzed data; and S.M.V. and E.V.M. wrote the paper.

Reviewers: E.B., University of Trento; and S.G., University of Rochester.

Conflict of interest statement: S.L.S. is a member of the Board of Directors of the Genomics Institute of the Novartis Research Foundation (“GNF”); a shareholder and member of the Board of Directors of Jnana Therapeutics; a shareholder of Forma Therapeutics; a shareholder of and adviser to Decibel Therapeutics and Eikonizo Therapeutics; an adviser to Eisai, Inc., the Ono Pharma Foundation, and F-Prime Capital Partners; and a Novartis Faculty Scholar.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1901947116/-/DCSupplemental.

Published under the PNAS license.

Keywords: Prions; Prion diseases; CJD.

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A novel #combination of #prion strain co-occurrence in #patients with sporadic #CJD (Am J Pathol., abstract)

[Source: The American Journal of Pathology, full page: (LINK). Abstract, edited.]

A novel combination of prion strain co-occurrence in patients with sporadic Creutzfeldt-Jakob disease

Atsushi Kobayashi 1,∗, Yasushi Iwasaki 2, Masaki Takao 3, Yuko Saito 4, Toru Iwaki 5, Zechen Qi 1, Ryouta Torimoto 1, Taishi Shimazaki 1, Yoshiko Munesue 1, Norikazu Isoda 6,7, Hirofumi Sawa 6,8, Keisuke Aoshima 1, Takashi Kimura 1, Hinako Kondo 9, Shirou Mohri 9, Tetsuyuki Kitamoto9

DOI: https://doi.org/10.1016/j.ajpath.2019.02.012

Published online: March 26, 2019 – Accepted: February 15, 2019 – Received in revised form: January 31, 2019 – Received: November 29, 2018

 

Abstract

Six subgroups of sporadic Creutzfeldt-Jakob disease have been identified by distinctive clinicopathological features, genotype at polymorphic codon 129 (methionine/valine, M/V) of the PRNP gene, and type of abnormal prion proteins (type 1 or 2). In addition to the pure subgroups, mixed neuropathological features and co-existence of two types of abnormal prion proteins in the same patient have also been reported. Here, we found that a portion of the patients previously diagnosed as MM1 had neuropathological characteristics of MM2 thalamic form, ie, neuronal loss of the inferior olivary nucleus of the medulla. Furthermore, co-existence of biochemical features of MM2 thalamic form was also confirmed in the identified cases. In addition, in transmission experiments using prion protein–humanized mice, the brain material from the identified case showed weak infectivity and generated characteristic abnormal prion proteins in the inoculated mice resembling those after inoculation with a brain material of MM2 thalamic form. Taken together, these results show that the co-occurrence of MM1 and MM2 thalamic form is a novel entity of sporadic Creutzfeldt-Jakob disease prion strain co-occurrence. The present study raises the possibility that the co-occurrence of MM2 thalamic form might have been overlooked so far due to scarcity of abnormal prion protein accumulation and restricted neuropathology.

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Funding: Supported by JSPS KAKENHI Grant Number 18K05963 (A.K.) and 18K06506 (M.T.), a grant from The Ichiro Kanehara Foundation (A.K.), a grant from The Suhara Memorial Foundation (A.K.), a grant from The Kato Memorial Trust for Nambyo Research (A.K.), Research Committee of Prion Disease and Slow Virus Infection, Research on Policy Planning and Evaluation for Rare and Intractable Diseases, Health and Labour Sciences Research Grants, The Ministry of Health, Labour and Welfare, Japan (M.T.), and AMED under Grant Number JP18dm0107103 (Y.S.).

Disclosures: None declared.

© 2019 Published by Elsevier Inc. on behalf of the American Society for Investigative Pathology.

Keywords: Prions; Creutzfeldt-Jakob Disease; Neurology.

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#Accumulation of #prion protein in the #vagus nerve in #CJD (

[Source: Annals of Neurology, full page: (LINK). Abstract, edited.]

Accumulation of prion protein in the vagus nerve in Creutzfeldt‐Jakob disease

Philip Kresl MD,  Jasmin Rahimi MD,  Ellen Gelpi MD PhD,  Iban Aldecoa MD PhD, Gerda Ricken MSc, Krisztina Danics MD,  Eva Keller MD PhD,  Gabor G. Kovacs MD PhD

First published: 23 February 2019 / DOI:  https://doi.org/10.1002/ana.25451

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/ana.25451.

 

Abstract

Disease‐associated proteins are thought to propagate along neuronal processes in neurodegenerative diseases. To detect disease‐associated prion protein (PrPSc) in the vagus nerve in different forms and molecular subtypes of Creutzfeldt‐Jakob disease (CJD) we applied three different anti‐PrP antibodies. We screened the vagus nerve in 162 sporadic and 30 genetic CJD cases. 4/31 VV‐2 type sporadic CJD and 7/30 genetic CJD cases showed vagal PrPSc immunodeposits with distinct morphology. Thus PrPSc in CJD affects the vagus nerve analogously to α‐synuclein in Parkinson’s disease. The morphologically diverse deposition of PrPSc in genetic and sporadic CJD argues against uniform mechanisms of propagation of PrPSc.

This article is protected by copyright. All rights reserved.

Keywords: Prions; CJD.

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EARLY‐ONSET #CEREBRAL #AMYLOID #ANGIOPATHY FOLLOWING #CHILDHOOD EXPOSURE TO CADAVERIC #DURA (Ann Neurol., abstract)

[Source: Annals of Neurology, full page: (LINK). Abstract, edited.]

EARLY‐ONSET CEREBRAL AMYLOID ANGIOPATHY FOLLOWING CHILDHOOD EXPOSURE TO CADAVERIC DURA

Gargi Banerjee MRCP,  Matthew E Adams FRCR,  Zane Jaunmuktane FRCPath, G. Alistair Lammie FRCPath,  Ben Turner MD, Mushtaq Wani FRCP,  Inder M S Sawhney DM, Henry Houlden MD,  Simon Mead PhD,  Sebastian Brandner MD FRCPath,  David J Werring FRCP

First published: 31 December 2018 / DOI:  https://doi.org/10.1002/ana.25407

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/ana.25407.

 

Abstract

Amyloid‐β transmission has been described in patients both with and without iatrogenic Creutzfeldt‐Jakob disease; however, there is little information regarding the impact of this acquired amyloid‐β pathology during life. Here, for the first time, we describe in detail the clinical and neuroimaging findings in three patients with early‐onset symptomatic amyloid‐β cerebral amyloid angiopathy following childhood exposure to cadaveric dura (by neurosurgical grafting in two patients, and tumour embolization in a third). Our observations provide further in vivo evidence that cerebral amyloid angiopathy might be caused by transmission of amyloid‐β seeds (prions) present in cadaveric dura, and has diagnostic relevance for younger patients presenting with suspected cerebral amyloid angiopathy.

This article is protected by copyright. All rights reserved.

Keywords: Prions; Amyloid angipopathy.

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