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Original Investigation
May 6, 2019

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

Author Affiliations
  • 1UCSF Memory and Aging Center, Department of Neurology, University of California, San Francisco
  • 2Department of Psychology, Palo Alto University, Palo Alto, California
  • 3Department of Neurology, Tongji Hospital affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  • 4Rocky Mountain Laboratories, National Institute of Allergy and Infectious Disease, National Institutes of Health, Hamilton, Montana
  • 5Department of Biostatistics and Epidemiology, University of California, San Francisco
  • 6Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  • 7Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden
  • 8Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
  • 9UK Dementia Research Institute, University College London, London, United Kingdom
JAMA Neurol. Published online May 6, 2019. 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.

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