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Plasma Neurofilament Light and Phosphorylated Tau 181 as Biomarkers of Alzheimer’s Disease Pathology and Clinical Disease Progression
Christopher Clark
Universitat Zurich
Corresponding Author
ORCiD: https://orcid.org/0000-0001-7210-7702
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: To assess the performance of plasma neurofilament light (NfL) and phosphorylated tau 181 (p-tau181) to inform about cerebral Alzheimer’s disease (AD) pathology and predict clinical progression in a memory clinic setting.
Methods: Plasma NfL and p-tau181, along with established cerebrospinal fluid (CSF) biomarkers of AD pathology (CSF β-amyloid 1-42 (Aβ1-42), Aβ1-42 /Aβ1-40, total-tau (tau), and p-tau181) were measured in participants with normal cognition (CN, n=91) and memory clinic patients with cognitive impairment (mild cognitive impairment and dementia, CI, n=127). Clinical and neuropsychological evaluations were performed at inclusion and follow-up visits at 18 and 36 months, to measure decline in global cognition and progression of disease severity. Multivariate analysis assessed associations of plasma NfL and p-tau181 levels with the presence of cerebral AD pathology (a priori defined by a CSF p-tau181/Aβ1-42 > 0.0779), single CSF biomarkers, and clinical measures of disease progression.
Results: Plasma NfL levels were higher in CN participants with an AD CSF profile, and in CI participants when compared to CN non-AD participants, while p-tau181 plasma levels were higher in CI patients with AD when compared to the other participants. Plasma NfL levels correlated with CSF tau and p-tau181 in CN, and with CSF tau in CI patients. Plasma p-tau181 correlated with CSF p-tau181 in CN and with CSF biomarkers in CI participants. Compared to a reference model, adding plasma p-tau181 improved the prediction of AD in CI patients (AUC 0.861, p-value = 0.048) while adding NfL did not. Adding p-tau181, but not NfL levels, to a reference model improved prediction of cognitive decline in CI participants (AUC 0.838, p-value = 0.032). Using a plasma p-tau181 cutoff of 9.68 pg/ml the models reached a sensitivity of 0.80 and specificity of 0.79 for AD prediction, and of 0.88 and 0.69 for the prediction of cognitive decline.
Conclusion: Plasma NfL may be useful as a marker of neuronal injury, although it is not specific for AD. P-tau181 can serve, in a memory clinic setting, as a blood-based biomarker of both cerebral AD pathology and cognitive decline. The predictive performance of both markers depends on the presence of cognitive impairment.
Keywords
Biomarkers, plasma, Alzheimer’s, neurofilament light, p-tau181
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CURRENT STATUS: Under Revision
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Posted 30 Dec, 2020
No community comments so far
Editorial decision: Major Revision
On 23 Jan, 2021
Review #2 received
Received 21 Jan, 2021
Review #1 received
Received 19 Jan, 2021
Reviewer #2 agreed
On 11 Jan, 2021
Reviewer #1 agreed
On 10 Jan, 2021
Reviewers invited
Invitations sent on 09 Jan, 2021
Editor assigned
On 23 Dec, 2020
Submission checks complete
On 23 Dec, 2020
Editor invited
On 23 Dec, 2020
First submitted
On 21 Dec, 2020
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Subject Areas
Cognitive Neuroscience
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This preprint is under consideration at Alzheimer's Research and Therapy. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Plasma Neurofilament Light and Phosphorylated Tau 181 as Biomarkers of Alzheimer’s Disease Pathology and Clinical Disease Progression
Christopher Clark
Universitat Zurich
Corresponding Author
ORCiD: https://orcid.org/0000-0001-7210-7702
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Revision
Version 1
Posted 30 Dec, 2020
No community comments so far
Editorial decision: Major Revision
On 23 Jan, 2021
Review #2 received
Received 21 Jan, 2021
Review #1 received
Received 19 Jan, 2021
Reviewer #2 agreed
On 11 Jan, 2021
Reviewer #1 agreed
On 10 Jan, 2021
Reviewers invited
Invitations sent on 09 Jan, 2021
Editor assigned
On 23 Dec, 2020
Submission checks complete
On 23 Dec, 2020
Editor invited
On 23 Dec, 2020
First submitted
On 21 Dec, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Cognitive Neuroscience
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: To assess the performance of plasma neurofilament light (NfL) and phosphorylated tau 181 (p-tau181) to inform about cerebral Alzheimer’s disease (AD) pathology and predict clinical progression in a memory clinic setting.
Methods: Plasma NfL and p-tau181, along with established cerebrospinal fluid (CSF) biomarkers of AD pathology (CSF β-amyloid 1-42 (Aβ1-42), Aβ1-42 /Aβ1-40, total-tau (tau), and p-tau181) were measured in participants with normal cognition (CN, n=91) and memory clinic patients with cognitive impairment (mild cognitive impairment and dementia, CI, n=127). Clinical and neuropsychological evaluations were performed at inclusion and follow-up visits at 18 and 36 months, to measure decline in global cognition and progression of disease severity. Multivariate analysis assessed associations of plasma NfL and p-tau181 levels with the presence of cerebral AD pathology (a priori defined by a CSF p-tau181/Aβ1-42 > 0.0779), single CSF biomarkers, and clinical measures of disease progression.
Results: Plasma NfL levels were higher in CN participants with an AD CSF profile, and in CI participants when compared to CN non-AD participants, while p-tau181 plasma levels were higher in CI patients with AD when compared to the other participants. Plasma NfL levels correlated with CSF tau and p-tau181 in CN, and with CSF tau in CI patients. Plasma p-tau181 correlated with CSF p-tau181 in CN and with CSF biomarkers in CI participants. Compared to a reference model, adding plasma p-tau181 improved the prediction of AD in CI patients (AUC 0.861, p-value = 0.048) while adding NfL did not. Adding p-tau181, but not NfL levels, to a reference model improved prediction of cognitive decline in CI participants (AUC 0.838, p-value = 0.032). Using a plasma p-tau181 cutoff of 9.68 pg/ml the models reached a sensitivity of 0.80 and specificity of 0.79 for AD prediction, and of 0.88 and 0.69 for the prediction of cognitive decline.
Conclusion: Plasma NfL may be useful as a marker of neuronal injury, although it is not specific for AD. P-tau181 can serve, in a memory clinic setting, as a blood-based biomarker of both cerebral AD pathology and cognitive decline. The predictive performance of both markers depends on the presence of cognitive impairment.
Figure 1
Figure 2
Figure 3