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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.


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.

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