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. 2021 Dec 14;13(1):199.
doi: 10.1186/s13195-021-00944-y.

Comparison of plasma neurofilament light and total tau as neurodegeneration markers: associations with cognitive and neuroimaging outcomes

Jordan D Marks  1 , Jeremy A Syrjanen  2 , Jonathan Graff-Radford  3 , Ronald C Petersen  2   3 , Mary M Machulda  4 , Michelle R Campbell  5 , Alicia Algeciras-Schimnich  5 , Val Lowe  6 , David S Knopman  3 , Clifford R Jack Jr  6 , Prashanthi Vemuri  6 , Michelle M Mielke  7   8 ; Alzheimer’s Disease Neuroimaging Initiative
Affiliations

Comparison of plasma neurofilament light and total tau as neurodegeneration markers: associations with cognitive and neuroimaging outcomes

Jordan D Marks et al. Alzheimers Res Ther. .

Abstract

Background: Total tau protein (T-Tau) and neurofilament light chain (NfL) have emerged as candidate plasma biomarkers of neurodegeneration, but studies have not compared how these biomarkers cross-sectionally or longitudinally associate with cognitive and neuroimaging measures. We therefore compared plasma T-Tau and NfL as cross-sectional and longitudinal markers of (1) global and domain-specific cognitive decline and (2) neuroimaging markers of cortical thickness, hippocampal volume, white matter integrity, and white matter hyperintensity volume.

Methods: We included 995 participants without dementia who were enrolled in the Mayo Clinic Study of Aging cohort. All had concurrent plasma NfL and T-tau, cognitive status, and neuroimaging data. Follow-up was repeated approximately every 15 months for a median of 6.2 years. Plasma NfL and T-tau were measured on the Simoa-HD1 Platform. Linear mixed effects models adjusted for age, sex, and education examined associations between baseline z-scored plasma NfL or T-tau and cognitive or neuroimaging outcomes. Analyses were replicated in Alzheimer's Disease Neuroimaging Initiative (ADNI) among 387 participants without dementia followed for a median of 3.0 years.

Results: At baseline, plasma NfL was more strongly associated with all cognitive and neuroimaging outcomes. The combination of having both elevated NfL and T-tau at baseline, compared to elevated levels of either alone, was more strongly associated at cross-section with worse global cognition and memory, and with neuroimaging measures including temporal cortex thickness and increased number of infarcts. In longitudinal analyses, baseline plasma T-tau did not add to the prognostic value of baseline plasma NfL. Results using ADNI data were similar.

Conclusions: Our results indicate plasma NfL had better utility as a prognostic marker of cognitive decline and neuroimaging changes. Plasma T-tau added cross-sectional value to NfL in specific contexts.

Trial registration: Not applicable.

Keywords: Blood-based biomarker; Cognition; Neurofilament light chain; Neuroimaging; Total tau.

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Conflict of interest statement

Dr. Knopman served on a Data Safety Monitoring Board for the DIAN study. He serves on a Data Safety monitoring Board for a tau therapeutic for Biogen, but receives no personal compensation. He is a site investigator in the Biogen aducanumab trials. He is an investigator in a clinical trial sponsored by Lilly Pharmaceuticals and the University of Southern California. He serves as a consultant for Samus Therapeutics, Third Rock, Roche and Alzeca Biosciences but receives no personal compensation. Dr. Lowe serves on scientific advisory boards for Bayer Schering Pharma, Philips Molecular lmaging, Life Molecular lmaging, AVID Radiopharamceuticals, and GE Healthcare and receives research support from GE Healthcare, Siemens Molecular Imaging, and AVID Radiopharmaceuticals. Dr. Jack serves on an independent data monitoring board for Roche, has served as a speaker for Eisai, and consulted for Biogen, but he receives no personal compensation from any commercial entity. Dr. Petersen is a consultant for Roche, Biogen, Merck, Eli Lilly, and Genentech. He receives publishing royalties from Mild Cognitive Impairment (Oxford University Press, 2003). Dr. Mielke is a consultant for Biogen, Brain Protection Company, and LabCorp on blood-based biomarkers. She serves on Editorial Boards for Alzheimer’s and Dementia, Neurology, and Alzheimer’s Research Therapy. All other authors report no conflicts of interest.

Figures

Fig. 1
Fig. 1
Relationships between plasma NfL or T-tau and cognition and neuroimaging in the MCSA. A Associations of baseline plasma NfL or T-tau with cognitive z-scores at cross-section. B Associations of baseline plasma NfL or T-tau with longitudinal cognitive outcomes. C Associations of baseline plasma NfL or T-tau with cross-sectional neuroimaging measures. D Associations of baseline plasma NfL or T-tau and longitudinal neuroimaging changes. Models adjust for age, sex, education, and whether or not the cognitive test had been previously administered. WMH volume and infarct measurements were log-transformed. Hippocampal volume measures were adjusted for total intracranial volume. Median follow-up was 6.2 years. Abbreviations: FA fractional anisotropy, NfL neurofilament light, T-tau total tau, WMH white matter hyperintensity
Fig. 2
Fig. 2
Amyloid-dependent associations between biomarkers with cross-sectional and longitudinal cognitive and neuroimaging outcomes in the MCSA. Relationships between plasma NfL or T-tau and cognition and neuroimaging in the MCSA stratified by amyloid-beta (Ab) status (elevated Ab PET, A+; non-elevated PET, A−). A Associations of baseline plasma NfL or T-tau with cognitive z-scores at cross-section. B Associations of baseline plasma NfL or T-tau with longitudinal cognitive outcomes. C Associations of baseline plasma NfL or T-tau with cross-sectional neuroimaging measures. D Associations of baseline plasma NfL or T-tau and longitudinal neuroimaging changes. Models adjust for age, sex, education, and whether or not the cognitive test had been previously administered. WMH volume and infarct measurements were log-transformed. Hippocampal volume measures were adjusted for total intracranial volume. Median follow-up in the cohort was 6.2 years. Abbreviations: FA fractional anisotropy, NfL neurofilament light, T-tau total tau, WMH white matter hyperintensity
Fig. 3
Fig. 3
Cross-sectional and longitudinal associations between plasma biomarkers and cognitive and imaging outcomes in ADNI. Relationships between plasma NfL or T-tau and cognition or neuroimaging in ADNI. A Associations at cross-section. B Associations over time (median follow-up 3.0 years). For the ADAS-Cog13 and Trail Making Test B, a higher score indicates worse performance. Models adjust for age, sex, and education. Hippocampal volume measures were adjusted for total intracranial volume. Abbreviations: ADAS Alzheimer’s disease assessment scale-cognitive subscale 13 tasks, ADNI Alzheimer’s Disease Neuroimaging Initiative, TMTB Trail Making Test Part B
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References

    1. Li D, Mielke MM. An update on blood-based markers of Alzheimer’s disease using the SiMoA platform. Neurol Ther. 2019;8:73–82. doi: 10.1007/s40120-019-00164-5. - DOI - PMC - PubMed
    1. Dage JL, Wennberg AM, Airey DC, Hagen CE, Knopman DS, Machulda MM, et al. Levels of tau protein in plasma are associated with neurodegeneration and cognitive function in a population-based elderly cohort. Alzheimers Dement. 2016;12:1226–1234. doi: 10.1016/j.jalz.2016.06.001. - DOI - PMC - PubMed
    1. Mattsson N, Zetterberg H, Janelidze S, Insel PS, Andreasson U, Stomrud E, et al. Plasma tau in Alzheimer disease. Neurology. 2016;87:1827–1835. doi: 10.1212/WNL.0000000000003246. - DOI - PMC - PubMed
    1. Osborn KE, Khan OA, Kresge HA, Bown CW, Liu D, Moore EE, et al. Cerebrospinal fluid and plasma neurofilament light relate to abnormal cognition. Alzheimers Dement (Amst) 2019;11:700–709. doi: 10.1016/j.dadm.2019.08.008. - DOI - PMC - PubMed
    1. Mattsson N, Cullen NC, Andreasson U, Zetterberg H, Blennow K. Association between longitudinal plasma neurofilament light and neurodegeneration in patients with Alzheimer disease. JAMA Neurol. 2019;76:791–799. doi: 10.1001/jamaneurol.2019.0765. - DOI - PMC - PubMed

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