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

Educational Objective
To determine whether fluid biomarkers can improve prediction of survival time in sporadic Creutzfeldt-Jakob disease beyond demographic and genetic biomarkers.
1 Credit CME
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.

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Article Information

Accepted for Publication: February 20, 2019.

Corresponding Author: Adam M. Staffaroni, PhD, UCSF Memory and Aging Center, Department of Neurology, University of California, San Francisco, 675 Nelson Rising Ln, Ste 190, San Francisco, CA 94158 (adam.staffaroni@ucsf.edu).

Published Online: May 6, 2019. doi:10.1001/jamaneurol.2019.1071

Author Contributions: Drs Staffaroni and Geschwind had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Staffaroni, Rosen, Geschwind.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Staffaroni, A. Kramer, Casey, Geschwind.

Critical revision of the manuscript for important intellectual content: Staffaroni, Kang, Rojas, Orrú, Caughey, Allen, J. Kramer, Rosen, Blennow, Zetterberg, Geschwind.

Statistical analysis: Staffaroni, A. Kramer, Allen.

Obtained funding: Caughey, Blennow, Zetterberg, Geschwind.

Administrative, technical, or material support: A. Kramer, Kang, Caughey, J. Kramer, Zetterberg.

Study supervision: Caughey, J. Kramer, Rosen, Geschwind.

Conflict of Interest Disclosures: Dr Staffaroni is supported by grants from the Larry H. Hillblom Foundation (2018-A-025-FEL) and the National Institutes of Health. Ms Casey had her salary paid through grants from the National Institutes of Health. Dr Kang was supported by a special fund for international exchange from Tonjii Hospital affiliated to Tongji Medical College, Huazhong University of Science and Technology. Dr Rojas is a site principal investigator for clinical trials supported by Eli Lilly and Company and receives support from the National Institutes of Health (grants AG038791, 75691348/A4, and AG23501). Dr Caughey is an inventor on US and EU patents for real-time quaking-induced conversion test assays that are owned by the United States of America, as represented by the Secretary, Department of Health and Human Services. Dr J. Kramer receives research support from National Institutes of Health, the Tau Consortium, and the Larry H. Hillblom Foundation and serves on a Biogen advisory board. Dr Rosen has received research support from Biogen Pharmaceuticals, has consulting agreements with Wave Neuroscience and Ionis Pharmaceuticals, and receives research support from the National Institutes of Health. Dr Blennow has received personal fees from Biogen, Eli Lilly and Company, Novartis, Roche Diagnostics, and CogRx for serving on advisory boards and as a consultant and is a cofounder of Brain Biomarker Solutions. Dr Zetterberg has received personal fees from CogRx, Samumed, Wave, and Roche Diagnostics for participating in scientific advisory boards and is a cofounder of Brain Biomarker Solutions. Dr Geschwind has received grants from the National Institute on Aging (grants K23 AG021989, P01 AG02160, and R01 AG AG031189), Alliance BioSecure, and Quest Diagnostics; research support from the Michael J. Homer Family Fund; consulting fees from Quest Diagnostics, 3M Communications, Advanced Medical, Best Doctors, Grand Rounds, Second Opinion, Gerson Lehrman Group, Guidepoint Global, MEDACorp, LCN Consulting, Optio Biopharma Solutions, Teva Pharmaceutical Industries, Biohaven Pharmaceuticals, In Thought, the US Department of Justice, and medical-legal consulting firms (Smith & Hennessey LLC, Boccardo Law LLC, and Kendrall Brill & Kelley LLP); speaking honoraria for various medical center lectures, from the American Academy of Neurology, and from Oakstone Publishing; past research support from Alliance BioSecure, CurePSP, the Tau Consortium, Quest Diagnostics, and the National Institutes of Health; and serves on the board of directors for San Francisco Bay Area Physicians for Social Responsibility and on the editorial board of Dementia & Neuropsychologia. No other disclosures were reported.

Funding/Support: This work was supported by grant R01 AG AG031189 from the National Institute on Aging, grant 2018-A-025-FEL from the Larry H. Hillblom Foundation, Alliance BioSecure, Michael J. Homer Family Fund, and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (Drs Orrú and Caughey).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank the patients and families for their involvement in research.

References
1.
Takada  LT, Geschwind  MD.  Prion diseases.  Semin Neurol. 2013;33(4):348-356. doi:10.1055/s-0033-1359314PubMedGoogle ScholarCrossref
2.
Ladogana  A, Puopolo  M, Croes  EA,  et al.  Mortality from Creutzfeldt-Jakob disease and related disorders in Europe, Australia, and Canada.  Neurology. 2005;64(9):1586-1591. doi:10.1212/01.WNL.0000160117.56690.B2PubMedGoogle ScholarCrossref
3.
Masters  CL, Harris  JO, Gajdusek  DC, Gibbs  CJ  Jr, Bernoulli  C, Asher  DM.  Creutzfeldt-Jakob disease: patterns of worldwide occurrence and the significance of familial and sporadic clustering.  Ann Neurol. 1979;5(2):177-188. doi:10.1002/ana.410050212PubMedGoogle ScholarCrossref
4.
Mead  S, Tagliavini  F.  Clinical trials.  Handb Clin Neurol. 2018;153:431-444. doi:10.1016/B978-0-444-63945-5.00024-6PubMedGoogle ScholarCrossref
5.
Johnson  DY, Dunkelberger  DL, Henry  M,  et al.  Sporadic Jakob-Creutzfeldt disease presenting as primary progressive aphasia.  JAMA Neurol. 2013;70(2):254-257. doi:10.1001/2013.jamaneurol.139PubMedGoogle ScholarCrossref
6.
Pocchiari  M, Puopolo  M, Croes  EA,  et al.  Predictors of survival in sporadic Creutzfeldt-Jakob disease and other human transmissible spongiform encephalopathies.  Brain. 2004;127(pt 10):2348-2359. doi:10.1093/brain/awh249PubMedGoogle ScholarCrossref
7.
Puoti  G, Bizzi  A, Forloni  G, Safar  JG, Tagliavini  F, Gambetti  P.  Sporadic human prion diseases: molecular insights and diagnosis.  Lancet Neurol. 2012;11(7):618-628. doi:10.1016/S1474-4422(12)70063-7PubMedGoogle ScholarCrossref
8.
Brown  P, Cathala  F, Castaigne  P, Gajdusek  DC.  Creutzfeldt-Jakob disease: clinical analysis of a consecutive series of 230 neuropathologically verified cases.  Ann Neurol. 1986;20(5):597-602. doi:10.1002/ana.410200507PubMedGoogle ScholarCrossref
9.
Collins  SJ, Sanchez-Juan  P, Masters  CL,  et al.  Determinants of diagnostic investigation sensitivities across the clinical spectrum of sporadic Creutzfeldt-Jakob disease.  Brain. 2006;129(pt 9):2278-2287. doi:10.1093/brain/awl159PubMedGoogle ScholarCrossref
10.
Parchi  P, Giese  A, Capellari  S,  et al.  Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects.  Ann Neurol. 1999;46(2):224-233. doi:10.1002/1531-8249(199908)46:2<224::AID-ANA12>3.0.CO;2-WPubMedGoogle ScholarCrossref
11.
White  AR, Enever  P, Tayebi  M,  et al.  Monoclonal antibodies inhibit prion replication and delay the development of prion disease.  Nature. 2003;422(6927):80-83. doi:10.1038/nature01457PubMedGoogle ScholarCrossref
12.
Trevitt  CR, Collinge  J.  A systematic review of prion therapeutics in experimental models.  Brain. 2006;129(pt 9):2241-2265. doi:10.1093/brain/awl150PubMedGoogle ScholarCrossref
13.
Wagner  J, Ryazanov  S, Leonov  A,  et al.  Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson’s disease.  Acta Neuropathol. 2013;125(6):795-813. doi:10.1007/s00401-013-1114-9PubMedGoogle ScholarCrossref
14.
Silber  BM, Rao  S, Fife  KL,  et al.  Pharmacokinetics and metabolism of 2-aminothiazoles with antiprion activity in mice.  Pharm Res. 2013;30(4):932-950. doi:10.1007/s11095-012-0912-4PubMedGoogle ScholarCrossref
15.
Jucker  M, Walker  LC.  Self-propagation of pathogenic protein aggregates in neurodegenerative diseases.  Nature. 2013;501(7465):45-51. doi:10.1038/nature12481PubMedGoogle ScholarCrossref
16.
Tsai  RM, Boxer  AL.  Therapy and clinical trials in frontotemporal dementia: past, present, and future.  J Neurochem. 2016;138(suppl 1):211-221. doi:10.1111/jnc.13640PubMedGoogle ScholarCrossref
17.
Mead  S, Burnell  M, Lowe  J,  et al.  Clinical trial simulations based on genetic stratification and the natural history of a functional outcome measure in Creutzfeldt-Jakob disease.  JAMA Neurol. 2016;73(4):447-455. doi:10.1001/jamaneurol.2015.4885PubMedGoogle ScholarCrossref
18.
Karch  A, Hermann  P, Ponto  C,  et al.  Cerebrospinal fluid tau levels are a marker for molecular subtype in sporadic Creutzfeldt-Jakob disease.  Neurobiol Aging. 2015;36(5):1964-1968. doi:10.1016/j.neurobiolaging.2015.01.021PubMedGoogle ScholarCrossref
19.
Skillbäck  T, Rosén  C, Asztely  F, Mattsson  N, Blennow  K, Zetterberg  H.  Diagnostic performance of cerebrospinal fluid total tau and phosphorylated tau in Creutzfeldt-Jakob disease: results from the Swedish Mortality Registry.  JAMA Neurol. 2014;71(4):476-483. doi:10.1001/jamaneurol.2013.6455PubMedGoogle ScholarCrossref
20.
Zerr  I, Schmitz  M, Karch  A,  et al.  Cerebrospinal fluid neurofilament light levels in neurodegenerative dementia: evaluation of diagnostic accuracy in the differential diagnosis of prion diseases.  Alzheimers Dement. 2018;14(6):751-763. doi:10.1016/j.jalz.2017.12.008PubMedGoogle ScholarCrossref
21.
Foutz  A, Appleby  BS, Hamlin  C,  et al.  Diagnostic and prognostic value of human prion detection in cerebrospinal fluid.  Ann Neurol. 2017;81(1):79-92. doi:10.1002/ana.24833PubMedGoogle ScholarCrossref
22.
Steinacker  P, Blennow  K, Halbgebauer  S,  et al.  Neurofilaments in blood and CSF for diagnosis and prediction of onset in Creutzfeldt-Jakob disease.  Sci Rep. 2016;6(1):38737. doi:10.1038/srep38737PubMedGoogle ScholarCrossref
23.
Thompson  AGB, Luk  C, Heslegrave  AJ,  et al.  Neurofilament light chain and tau concentrations are markedly increased in the serum of patients with sporadic Creutzfeldt-Jakob disease, and tau correlates with rate of disease progression.  J Neurol Neurosurg Psychiatry. 2018;89(9):955-961. doi:10.1136/jnnp-2017-317793PubMedGoogle ScholarCrossref
24.
Kovacs  GG, Andreasson  U, Liman  V,  et al.  Plasma and cerebrospinal fluid tau and neurofilament concentrations in rapidly progressive neurological syndromes: a neuropathology-based cohort.  Eur J Neurol. 2017;24(11):1326-e77. doi:10.1111/ene.13389PubMedGoogle ScholarCrossref
25.
Randall  J, Mörtberg  E, Provuncher  GK,  et al.  Tau proteins in serum predict neurological outcome after hypoxic brain injury from cardiac arrest: results of a pilot study.  Resuscitation. 2013;84(3):351-356. doi:10.1016/j.resuscitation.2012.07.027PubMedGoogle ScholarCrossref
26.
Franz  G, Beer  R, Kampfl  A,  et al.  Amyloid beta 1-42 and tau in cerebrospinal fluid after severe traumatic brain injury.  Neurology. 2003;60(9):1457-1461. doi:10.1212/01.WNL.0000063313.57292.00PubMedGoogle ScholarCrossref
27.
Zetterberg  H.  Review: tau in biofluids: relation to pathology, imaging and clinical features.  Neuropathol Appl Neurobiol. 2017;43(3):194-199. doi:10.1111/nan.12378PubMedGoogle ScholarCrossref
28.
Mattsson  N, Zetterberg  H, Bianconi  S,  et al.  Gamma-secretase-dependent amyloid-beta is increased in Niemann-Pick type C: a cross-sectional study.  Neurology. 2011;76(4):366-372. doi:10.1212/WNL.0b013e318208f4abPubMedGoogle ScholarCrossref
29.
Tousseyn  T, Bajsarowicz  K, Sánchez  H,  et al.  Prion disease induces Alzheimer disease-like neuropathologic changes.  J Neuropathol Exp Neurol. 2015;74(9):873-888. doi:10.1097/NEN.0000000000000228PubMedGoogle ScholarCrossref
30.
Chohan  G, Pennington  C, Mackenzie  JM,  et al.  The role of cerebrospinal fluid 14-3-3 and other proteins in the diagnosis of sporadic Creutzfeldt-Jakob disease in the UK: a 10-year review.  J Neurol Neurosurg Psychiatry. 2010;81(11):1243-1248. doi:10.1136/jnnp.2009.197962PubMedGoogle ScholarCrossref
31.
Forner  SA, Takada  LT, Bettcher  BM,  et al.  Comparing CSF biomarkers and brain MRI in the diagnosis of sporadic Creutzfeldt-Jakob disease.  Neurol Clin Pract. 2015;5(2):116-125. doi:10.1212/CPJ.0000000000000111PubMedGoogle ScholarCrossref
32.
Noguchi-Shinohara  M, Hamaguchi  T, Nozaki  I, Sakai  K, Yamada  M.  Serum tau protein as a marker for the diagnosis of Creutzfeldt-Jakob disease.  J Neurol. 2011;258(8):1464-1468. doi:10.1007/s00415-011-5960-xPubMedGoogle ScholarCrossref
33.
Foiani  MS, Woollacott  IO, Heller  C,  et al.  Plasma tau is increased in frontotemporal dementia.  J Neurol Neurosurg Psychiatry. 2018;89(8):804-807. doi:10.1136/jnnp-2017-317260PubMedGoogle ScholarCrossref
34.
Mattsson  N, Zetterberg  H, Janelidze  S,  et al; ADNI Investigators.  Plasma tau in Alzheimer disease.  Neurology. 2016;87(17):1827-1835. doi:10.1212/WNL.0000000000003246PubMedGoogle ScholarCrossref
35.
Mielke  MM, Hagen  CE, Wennberg  AMV,  et al.  Association of plasma total tau level with cognitive decline and risk of mild cognitive impairment or dementia in the Mayo Clinic Study on Aging.  JAMA Neurol. 2017;74(9):1073-1080. doi:10.1001/jamaneurol.2017.1359PubMedGoogle ScholarCrossref
36.
Zetterberg  H, Blennow  K.  From cerebrospinal fluid to blood: the third wave of fluid biomarkers for Alzheimer’s disease.  J Alzheimers Dis. 2018;64(s1):S271-S279. doi:10.3233/JAD-179926PubMedGoogle ScholarCrossref
37.
Zetterberg  H, Wilson  D, Andreasson  U,  et al.  Plasma tau levels in Alzheimer’s disease.  Alzheimers Res Ther. 2013;5(2):9. doi:10.1186/alzrt163PubMedGoogle ScholarCrossref
38.
Zetterberg  H, Blennow  K.  Chronic traumatic encephalopathy: fluid biomarkers.  Handb Clin Neurol. 2018;158:323-333. doi:10.1016/B978-0-444-63954-7.00030-6PubMedGoogle ScholarCrossref
39.
Dorey  A, Tholance  Y, Vighetto  A,  et al.  Association of cerebrospinal fluid prion protein levels and the distinction between Alzheimer disease and Creutzfeldt-Jakob disease.  JAMA Neurol. 2015;72(3):267-275. doi:10.1001/jamaneurol.2014.4068PubMedGoogle ScholarCrossref
40.
Palmer  MS, Dryden  AJ, Hughes  JT, Collinge  J.  Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease.  Nature. 1991;352(6333):340-342. doi:10.1038/352340a0PubMedGoogle ScholarCrossref
41.
Collinge  J, Clarke  AR.  A general model of prion strains and their pathogenicity.  Science. 2007;318(5852):930-936. doi:10.1126/science.1138718PubMedGoogle ScholarCrossref
42.
Shaw  LM, Arias  J, Blennow  K,  et al.  Appropriate use criteria for lumbar puncture and cerebrospinal fluid testing in the diagnosis of Alzheimer’s disease.  Alzheimers Dement. 2018;14(11):1505-1521. doi:10.1016/j.jalz.2018.07.220PubMedGoogle ScholarCrossref
43.
Mattsson  N, Andreasson  U, Zetterberg  H, Blennow  K; Alzheimer’s Disease Neuroimaging Initiative.  Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease.  JAMA Neurol. 2017;74(5):557-566. doi:10.1001/jamaneurol.2016.6117PubMedGoogle ScholarCrossref
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