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, according to research published online ahead of print May 6 in JAMA Neurology. Levels of total tau in plasma and CSF are correlated, and plasma total tau is associated with survival time. These findings suggest that plasma total tau level could be a valid biomarker that guides clinical care for patients with sporadic Creutzfeldt-Jakob disease, said the investigators.
The accurate prediction of disease duration can assist clinicians and caregivers in clinical management, as well as influence the design of clinical trials. Previous studies have found that baseline protein levels in CSF and plasma are associated with disease duration in patients with sporadic Creutzfeldt-Jakob disease. To replicate these findings, Adam M. Staffaroni, PhD, of the department of neurology at the University of California, San Francisco, and colleagues conducted a longitudinal cohort study.
Evaluating fluid and nonfluid biomarkers
Dr. Staffaroni and colleagues recruited 193 participants with probable or definite sporadic Creutzfeldt-Jakob disease who had codon 129 genotyping and were referred to the UCSF Memory and Aging Center from March 2004 to January 2018. All participants underwent cognitive testing, informant measures, a neurologic examination, and CSF and blood sample collection. The researchers excluded from analysis five participants who had been placed on life-extending treatments. Participants were evaluated until death or censored at the time of statistical analysis.
Dr. Staffaroni and colleagues examined the following nonfluid biomarkers of survival: sex, age, codon 129 genotype, Barthel Index, and Medical Research Council (MRC) Prion Disease Rating Scale. In addition, they examined total tau level, phosphorylated tau level, total tau:phosphorylated tau ratio, neurofilament light (NfL) level, beta-amyloid 42 level, neuron-specific enolase level, 14-3-3 test result, and real-time quaking-induced conversion test in CSF as fluid biomarkers of survival. Finally, Dr. Staffaroni’s group analyzed total tau level, NfL level, and glial fibrillary acidic protein level in plasma as additional fluid biomarkers of survival.
The researchers fitted Cox proportional hazard models with time to event as the outcome. They log-transformed fluid biomarkers and ran models with and without nonfluid biomarkers of survival.
Plasma total tau was associated with survival
In all, 188 patients were included in the analysis. The population’s mean age was 63.8 years. Approximately 45% of participants were women. The diagnosis of sporadic Creutzfeldt-Jakob disease was pathologically confirmed for 78.2% of participants and probable for 21.8% of participants.
Dr. Staffaroni’s group observed strong correlations between plasma and CSF NfL concentrations and between plasma and CSF total tau concentrations. CSF total tau and CSF NfL concentrations were also correlated.
Among the nonfluid biomarkers, Barthel Index, MRC Scale, and codon 129 genotype were significantly associated with survival time. Lower level of function at baseline predicted a faster disease course.
Among the fluid biomarkers, greater levels of plasma total tau and NfL levels at baseline were associated with shorter survival. After the investigators controlled for Barthel Index and codon 129 genotype, the association of plasma total tau level with survival time remained significant. Plasma total tau level and Barthel Index (hazard ratio, 0.98) each independently predicted survival. Dr. Staffaroni and colleagues found that the hazard ratios for all CSF biomarkers were in the expected direction, and that those for total tau level, total tau:phosphorylated tau ratio, NfL level, and neuron-specific enolase level were statistically significant. Furthermore, positive results for 14-3-3 protein, neuron-specific enolase level, and total tau level were associated with a shorter time until death. Like the plasma biomarkers, CSF total tau level remained associated with survival after the investigators controlled for Barthel Index and codon 129 genotype. The same was true of CSF total tau:phosphorylated tau ratio, neuron-specific enolase level, and 14-3-3 result.
Plasma tau could be a diagnostic biomarker
“The hazard ratio associated with plasma total tau level was more than 40% higher than other fluid biomarkers of interest,” said the authors. “These findings further bolster the value of blood-based biomarkers, based on their minimally invasive and relatively inexpensive nature, and build on prior studies that suggested patients with sporadic Creutzfeldt-Jakob disease and controls can be discriminated with relatively high accuracy using blood-based assays.” When Dr. Staffaroni and colleagues modeled baseline functional status and plasma total tau levels together, they found that both were independent predictors of survival time. “This [finding] suggests that clinical measures and plasma total tau level could be combined to further improve prediction accuracy.”
Among the study’s limitations was its comparatively small subsample of patients for whom all plasma and CSF biomarkers were available. Disease duration and survival were longer in the study population than in the literature. “Another limitation is that the plasma biomarkers in this study, one of which showed great promise for predicting survival, were assayed using a research protocol,” said the researchers. “Widespread clinical use of these biomarkers will require well-validated commercial assays, development of which is underway.”
Before these biomarkers can be used in the clinic, these results will need to be replicated, and neurologists will need to develop consensus cutoffs for the biomarker levels. The researchers did not analyze plasma tau level as a diagnostic biomarker, but future studies should examine this potential, Dr. Staffaroni and colleagues concluded.
Grants from the National Institute on Aging and the National Institute of Allergy and Infectious Diseases supported the study.
SOURCE: Staffaroni AM et al. JAMA Neurol. 2019 May 6. doi: 10.1001/jamaneurol.2019.1071.
, according to research published online ahead of print May 6 in JAMA Neurology. Levels of total tau in plasma and CSF are correlated, and plasma total tau is associated with survival time. These findings suggest that plasma total tau level could be a valid biomarker that guides clinical care for patients with sporadic Creutzfeldt-Jakob disease, said the investigators.
The accurate prediction of disease duration can assist clinicians and caregivers in clinical management, as well as influence the design of clinical trials. Previous studies have found that baseline protein levels in CSF and plasma are associated with disease duration in patients with sporadic Creutzfeldt-Jakob disease. To replicate these findings, Adam M. Staffaroni, PhD, of the department of neurology at the University of California, San Francisco, and colleagues conducted a longitudinal cohort study.
Evaluating fluid and nonfluid biomarkers
Dr. Staffaroni and colleagues recruited 193 participants with probable or definite sporadic Creutzfeldt-Jakob disease who had codon 129 genotyping and were referred to the UCSF Memory and Aging Center from March 2004 to January 2018. All participants underwent cognitive testing, informant measures, a neurologic examination, and CSF and blood sample collection. The researchers excluded from analysis five participants who had been placed on life-extending treatments. Participants were evaluated until death or censored at the time of statistical analysis.
Dr. Staffaroni and colleagues examined the following nonfluid biomarkers of survival: sex, age, codon 129 genotype, Barthel Index, and Medical Research Council (MRC) Prion Disease Rating Scale. In addition, they examined total tau level, phosphorylated tau level, total tau:phosphorylated tau ratio, neurofilament light (NfL) level, beta-amyloid 42 level, neuron-specific enolase level, 14-3-3 test result, and real-time quaking-induced conversion test in CSF as fluid biomarkers of survival. Finally, Dr. Staffaroni’s group analyzed total tau level, NfL level, and glial fibrillary acidic protein level in plasma as additional fluid biomarkers of survival.
The researchers fitted Cox proportional hazard models with time to event as the outcome. They log-transformed fluid biomarkers and ran models with and without nonfluid biomarkers of survival.
Plasma total tau was associated with survival
In all, 188 patients were included in the analysis. The population’s mean age was 63.8 years. Approximately 45% of participants were women. The diagnosis of sporadic Creutzfeldt-Jakob disease was pathologically confirmed for 78.2% of participants and probable for 21.8% of participants.
Dr. Staffaroni’s group observed strong correlations between plasma and CSF NfL concentrations and between plasma and CSF total tau concentrations. CSF total tau and CSF NfL concentrations were also correlated.
Among the nonfluid biomarkers, Barthel Index, MRC Scale, and codon 129 genotype were significantly associated with survival time. Lower level of function at baseline predicted a faster disease course.
Among the fluid biomarkers, greater levels of plasma total tau and NfL levels at baseline were associated with shorter survival. After the investigators controlled for Barthel Index and codon 129 genotype, the association of plasma total tau level with survival time remained significant. Plasma total tau level and Barthel Index (hazard ratio, 0.98) each independently predicted survival. Dr. Staffaroni and colleagues found that the hazard ratios for all CSF biomarkers were in the expected direction, and that those for total tau level, total tau:phosphorylated tau ratio, NfL level, and neuron-specific enolase level were statistically significant. Furthermore, positive results for 14-3-3 protein, neuron-specific enolase level, and total tau level were associated with a shorter time until death. Like the plasma biomarkers, CSF total tau level remained associated with survival after the investigators controlled for Barthel Index and codon 129 genotype. The same was true of CSF total tau:phosphorylated tau ratio, neuron-specific enolase level, and 14-3-3 result.
Plasma tau could be a diagnostic biomarker
“The hazard ratio associated with plasma total tau level was more than 40% higher than other fluid biomarkers of interest,” said the authors. “These findings further bolster the value of blood-based biomarkers, based on their minimally invasive and relatively inexpensive nature, and build on prior studies that suggested patients with sporadic Creutzfeldt-Jakob disease and controls can be discriminated with relatively high accuracy using blood-based assays.” When Dr. Staffaroni and colleagues modeled baseline functional status and plasma total tau levels together, they found that both were independent predictors of survival time. “This [finding] suggests that clinical measures and plasma total tau level could be combined to further improve prediction accuracy.”
Among the study’s limitations was its comparatively small subsample of patients for whom all plasma and CSF biomarkers were available. Disease duration and survival were longer in the study population than in the literature. “Another limitation is that the plasma biomarkers in this study, one of which showed great promise for predicting survival, were assayed using a research protocol,” said the researchers. “Widespread clinical use of these biomarkers will require well-validated commercial assays, development of which is underway.”
Before these biomarkers can be used in the clinic, these results will need to be replicated, and neurologists will need to develop consensus cutoffs for the biomarker levels. The researchers did not analyze plasma tau level as a diagnostic biomarker, but future studies should examine this potential, Dr. Staffaroni and colleagues concluded.
Grants from the National Institute on Aging and the National Institute of Allergy and Infectious Diseases supported the study.
SOURCE: Staffaroni AM et al. JAMA Neurol. 2019 May 6. doi: 10.1001/jamaneurol.2019.1071.
, according to research published online ahead of print May 6 in JAMA Neurology. Levels of total tau in plasma and CSF are correlated, and plasma total tau is associated with survival time. These findings suggest that plasma total tau level could be a valid biomarker that guides clinical care for patients with sporadic Creutzfeldt-Jakob disease, said the investigators.
The accurate prediction of disease duration can assist clinicians and caregivers in clinical management, as well as influence the design of clinical trials. Previous studies have found that baseline protein levels in CSF and plasma are associated with disease duration in patients with sporadic Creutzfeldt-Jakob disease. To replicate these findings, Adam M. Staffaroni, PhD, of the department of neurology at the University of California, San Francisco, and colleagues conducted a longitudinal cohort study.
Evaluating fluid and nonfluid biomarkers
Dr. Staffaroni and colleagues recruited 193 participants with probable or definite sporadic Creutzfeldt-Jakob disease who had codon 129 genotyping and were referred to the UCSF Memory and Aging Center from March 2004 to January 2018. All participants underwent cognitive testing, informant measures, a neurologic examination, and CSF and blood sample collection. The researchers excluded from analysis five participants who had been placed on life-extending treatments. Participants were evaluated until death or censored at the time of statistical analysis.
Dr. Staffaroni and colleagues examined the following nonfluid biomarkers of survival: sex, age, codon 129 genotype, Barthel Index, and Medical Research Council (MRC) Prion Disease Rating Scale. In addition, they examined total tau level, phosphorylated tau level, total tau:phosphorylated tau ratio, neurofilament light (NfL) level, beta-amyloid 42 level, neuron-specific enolase level, 14-3-3 test result, and real-time quaking-induced conversion test in CSF as fluid biomarkers of survival. Finally, Dr. Staffaroni’s group analyzed total tau level, NfL level, and glial fibrillary acidic protein level in plasma as additional fluid biomarkers of survival.
The researchers fitted Cox proportional hazard models with time to event as the outcome. They log-transformed fluid biomarkers and ran models with and without nonfluid biomarkers of survival.
Plasma total tau was associated with survival
In all, 188 patients were included in the analysis. The population’s mean age was 63.8 years. Approximately 45% of participants were women. The diagnosis of sporadic Creutzfeldt-Jakob disease was pathologically confirmed for 78.2% of participants and probable for 21.8% of participants.
Dr. Staffaroni’s group observed strong correlations between plasma and CSF NfL concentrations and between plasma and CSF total tau concentrations. CSF total tau and CSF NfL concentrations were also correlated.
Among the nonfluid biomarkers, Barthel Index, MRC Scale, and codon 129 genotype were significantly associated with survival time. Lower level of function at baseline predicted a faster disease course.
Among the fluid biomarkers, greater levels of plasma total tau and NfL levels at baseline were associated with shorter survival. After the investigators controlled for Barthel Index and codon 129 genotype, the association of plasma total tau level with survival time remained significant. Plasma total tau level and Barthel Index (hazard ratio, 0.98) each independently predicted survival. Dr. Staffaroni and colleagues found that the hazard ratios for all CSF biomarkers were in the expected direction, and that those for total tau level, total tau:phosphorylated tau ratio, NfL level, and neuron-specific enolase level were statistically significant. Furthermore, positive results for 14-3-3 protein, neuron-specific enolase level, and total tau level were associated with a shorter time until death. Like the plasma biomarkers, CSF total tau level remained associated with survival after the investigators controlled for Barthel Index and codon 129 genotype. The same was true of CSF total tau:phosphorylated tau ratio, neuron-specific enolase level, and 14-3-3 result.
Plasma tau could be a diagnostic biomarker
“The hazard ratio associated with plasma total tau level was more than 40% higher than other fluid biomarkers of interest,” said the authors. “These findings further bolster the value of blood-based biomarkers, based on their minimally invasive and relatively inexpensive nature, and build on prior studies that suggested patients with sporadic Creutzfeldt-Jakob disease and controls can be discriminated with relatively high accuracy using blood-based assays.” When Dr. Staffaroni and colleagues modeled baseline functional status and plasma total tau levels together, they found that both were independent predictors of survival time. “This [finding] suggests that clinical measures and plasma total tau level could be combined to further improve prediction accuracy.”
Among the study’s limitations was its comparatively small subsample of patients for whom all plasma and CSF biomarkers were available. Disease duration and survival were longer in the study population than in the literature. “Another limitation is that the plasma biomarkers in this study, one of which showed great promise for predicting survival, were assayed using a research protocol,” said the researchers. “Widespread clinical use of these biomarkers will require well-validated commercial assays, development of which is underway.”
Before these biomarkers can be used in the clinic, these results will need to be replicated, and neurologists will need to develop consensus cutoffs for the biomarker levels. The researchers did not analyze plasma tau level as a diagnostic biomarker, but future studies should examine this potential, Dr. Staffaroni and colleagues concluded.
Grants from the National Institute on Aging and the National Institute of Allergy and Infectious Diseases supported the study.
SOURCE: Staffaroni AM et al. JAMA Neurol. 2019 May 6. doi: 10.1001/jamaneurol.2019.1071.
FROM JAMA NEUROLOGY
Key clinical point: Invasive and minimally invasive biomarkers are associated with survival in sporadic Creutzfeldt-Jakob disease.
Major finding: The hazard ratio for plasma total tau level was more than 40% larger than any other biomarker.
Study details: A longitudinal study of 188 participants with sporadic Creutzfeldt-Jakob disease.
Disclosures: Grants from the National Institute on Aging and the National Institute of Allergy and Infectious Diseases supported the study.
Source: Staffaroni AM et al. JAMA Neurol. 2019 May 6. doi: 10.1001/jamaneurol.2019.1071.