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September 14, 2018

Serum neurofilament light
A biomarker of neuroaxonal injury after ischemic stroke

Steffen Tiedt, MD, Marco Duering, MD, Christian Barro, MD, Asli Gizem Kaya, MSc, Julia Boeck, Felix J. Bode, MD, Matthias Klein, MD, … Show All … , Franziska Dorn, MD, Benno Gesierich, PhD, Lars Kellert, MD, Birgit Ertl-Wagner, MD, Michael W. Goertler, MD, Gabor C. Petzold, MD, Jens Kuhle, MD, Frank A. Wollenweber, MD, Nils Peters, MD, and Martin Dichgans, MDAuthors Info & Affiliations
October 2, 2018 issue
91 (14) e1338-e1347
https://doi.org/10.1212/WNL.0000000000006282
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Abstract

Objective

To explore the utility of serum neurofilament light chain (NfL) as a biomarker for primary and secondary neuroaxonal injury after ischemic stroke (IS) and study its value for the prediction of clinical outcome.

Methods

We used an ultrasensitive single-molecule array assay to measure serum NfL levels in healthy controls (n = 30) and 2 independent cohorts of patients with IS: (1) with serial serum sampling at hospital arrival (n = 196), at days 2, 3, and 7 (n = 89), and up to 6 months post stroke; and (2) with standardized MRI at baseline and at 6 months post stroke, and with cross-sectional serum sampling at 6 months (n = 95). We determined the temporal profile of serum NfL levels, their association with imaging markers of neuroaxonal injury, and with clinical outcome.

Results

Patients with IS had higher serum NfL levels compared with healthy controls starting from admission until 6 months post stroke. Serum NfL levels peaked at day 7 (211.2 pg/mL [104.7–442.6], median [IQR]) and correlated with infarct volumes (day 7: partial r = 0.736, p = 1.5 × 10−15). Six months post stroke, patients with recurrent ischemic lesions on MRI (n = 19) had higher serum NfL levels compared to those without new lesions (n = 76, p = 0.002). Serum NfL levels 6 months post stroke further correlated with a quantitative measure of secondary neurodegeneration obtained from diffusion tensor imaging MRI (r = 0.361, p = 0.001). Serum NfL levels 7 days post stroke independently predicted modified Rankin Scale scores 3 months post stroke (cumulative odds ratio [95% confidence interval] = 2.35 [1.60–3.45]; p = 1.24 × 10−05).

Conclusion

Serum NfL holds promise as a biomarker for monitoring primary and secondary neuroaxonal injury after IS and for predicting functional outcome.

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Publication history

Received by Neurology January 24, 2018. Accepted in final form July 4, 2018.

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Information & Authors

Information

Published In

Neurology®
Volume 91 • Number 14 • October 2, 2018
Pages: e1338-e1347
PubMed: 30217937

Copyright

© 2018 American Academy of Neurology.

Publication History

Received: January 24, 2018
Accepted: July 4, 2018
Published online: September 14, 2018
Published in print: October 2, 2018

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Disclosure

The authors report no disclosures relevant to the manuscript. Go to Neurology.org/N for full disclosures.

Study Funding

M. Dichgans was supported by grants from the Deutsche Forschungsgemeinschaft (CRC 1123 [B3] and Munich Cluster for Systems Neurology [SyNergy]), the German Federal Ministry of Education and Research (BMBF, e:Med programme e:AtheroSysMed), the FP7/2007-2103 European Union project CVgenes@target (grant agreement no. Health-F2-2013-601456), the European Union Horizon2020 projects SVDs@target (grant agreement no. 66688) and CoSTREAM (grant agreement no. 667375), the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain), the Vascular Dementia Research Foundation, and the Jackstaedt Foundation. S.T. was supported by the Josef-Hackl-Stiftung and by a grant from the Deutsche Forschungsgemeinschaft (Munich Cluster for Systems Neurology [SyNergy]). J.K. was supported by the Swiss National Research Foundation (320030_160221). N.P. was supported by the Neurology Research Pool (University Hospital Basel). M. Duering was supported by grants from the Alzheimer Forschung Initiative e.V. (#16018CB) and the German Research Foundation (DFG DU1626/1-1).

Authors

Affiliations & Disclosures

Steffen Tiedt, MD*
From the Institute for Stroke and Dementia Research, University Hospital (S.T., M. Duering, A.G.K., J.B., B.G., F.A.W., M. Dichgans), and Graduate School of Systemic Neurosciences (S.T.), LMU Munich; Munich Cluster for Systems Neurology (SyNergy) (S.T., M. Dichgans), Munich, Germany; Neurologic Clinic and Policlinic (C.B., J.K.), Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Switzerland; German Center for Neurodegenerative Diseases (DZNE) (F.J.B., G.C.P.), Bonn; Department of Neurology (F.J.B., G.C.P.), University Hospital Bonn; Departments of Neurology (M.K., L.K.), Neuroradiology (F.D.), and Radiology (B.E.-W.), University Hospital, LMU Munich; Department of Neurology (M.W.G.), University of Magdeburg, University Hospital; German Center for Neurodegenerative Diseases (DZNE) (M.W.G.), Magdeburg, Germany; Stroke Center and Department of Neurology (N.P.), University Hospital Basel, Switzerland; and German Center for Neurodegenerative Diseases (DZNE) (M. Dichgans), Munich, Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
(1) Deutsche Forschungsgemeinschaft (Munich Cluster for Systems Neurology [SyNergy]), 2017-2018
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
(1) Josef-Hackl-Stiftung
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
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1.
NONE
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Marco Duering, MD*
From the Institute for Stroke and Dementia Research, University Hospital (S.T., M. Duering, A.G.K., J.B., B.G., F.A.W., M. Dichgans), and Graduate School of Systemic Neurosciences (S.T.), LMU Munich; Munich Cluster for Systems Neurology (SyNergy) (S.T., M. Dichgans), Munich, Germany; Neurologic Clinic and Policlinic (C.B., J.K.), Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Switzerland; German Center for Neurodegenerative Diseases (DZNE) (F.J.B., G.C.P.), Bonn; Department of Neurology (F.J.B., G.C.P.), University Hospital Bonn; Departments of Neurology (M.K., L.K.), Neuroradiology (F.D.), and Radiology (B.E.-W.), University Hospital, LMU Munich; Department of Neurology (M.W.G.), University of Magdeburg, University Hospital; German Center for Neurodegenerative Diseases (DZNE) (M.W.G.), Magdeburg, Germany; Stroke Center and Department of Neurology (N.P.), University Hospital Basel, Switzerland; and German Center for Neurodegenerative Diseases (DZNE) (M. Dichgans), Munich, Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
(1) Bayer Vital GmbH, speaker honoraria (2) Pfizer Pharma GmbH, speaker honoraria
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
(1) German Research Foundation (DFG), DU 1626/1-1, PI, 2017-2020
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
(1) Vascular Dementia Research Foundation, (2) Else Kr?ner-Fresenius- Stiftung, 2014-A200, PI, 2015-2017
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
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Christian Barro, MD
From the Institute for Stroke and Dementia Research, University Hospital (S.T., M. Duering, A.G.K., J.B., B.G., F.A.W., M. Dichgans), and Graduate School of Systemic Neurosciences (S.T.), LMU Munich; Munich Cluster for Systems Neurology (SyNergy) (S.T., M. Dichgans), Munich, Germany; Neurologic Clinic and Policlinic (C.B., J.K.), Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Switzerland; German Center for Neurodegenerative Diseases (DZNE) (F.J.B., G.C.P.), Bonn; Department of Neurology (F.J.B., G.C.P.), University Hospital Bonn; Departments of Neurology (M.K., L.K.), Neuroradiology (F.D.), and Radiology (B.E.-W.), University Hospital, LMU Munich; Department of Neurology (M.W.G.), University of Magdeburg, University Hospital; German Center for Neurodegenerative Diseases (DZNE) (M.W.G.), Magdeburg, Germany; Stroke Center and Department of Neurology (N.P.), University Hospital Basel, Switzerland; and German Center for Neurodegenerative Diseases (DZNE) (M. Dichgans), Munich, Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
Travel support by Novartis.
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
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Asli Gizem Kaya, MSc
From the Institute for Stroke and Dementia Research, University Hospital (S.T., M. Duering, A.G.K., J.B., B.G., F.A.W., M. Dichgans), and Graduate School of Systemic Neurosciences (S.T.), LMU Munich; Munich Cluster for Systems Neurology (SyNergy) (S.T., M. Dichgans), Munich, Germany; Neurologic Clinic and Policlinic (C.B., J.K.), Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Switzerland; German Center for Neurodegenerative Diseases (DZNE) (F.J.B., G.C.P.), Bonn; Department of Neurology (F.J.B., G.C.P.), University Hospital Bonn; Departments of Neurology (M.K., L.K.), Neuroradiology (F.D.), and Radiology (B.E.-W.), University Hospital, LMU Munich; Department of Neurology (M.W.G.), University of Magdeburg, University Hospital; German Center for Neurodegenerative Diseases (DZNE) (M.W.G.), Magdeburg, Germany; Stroke Center and Department of Neurology (N.P.), University Hospital Basel, Switzerland; and German Center for Neurodegenerative Diseases (DZNE) (M. Dichgans), Munich, Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
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Julia Boeck
From the Institute for Stroke and Dementia Research, University Hospital (S.T., M. Duering, A.G.K., J.B., B.G., F.A.W., M. Dichgans), and Graduate School of Systemic Neurosciences (S.T.), LMU Munich; Munich Cluster for Systems Neurology (SyNergy) (S.T., M. Dichgans), Munich, Germany; Neurologic Clinic and Policlinic (C.B., J.K.), Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Switzerland; German Center for Neurodegenerative Diseases (DZNE) (F.J.B., G.C.P.), Bonn; Department of Neurology (F.J.B., G.C.P.), University Hospital Bonn; Departments of Neurology (M.K., L.K.), Neuroradiology (F.D.), and Radiology (B.E.-W.), University Hospital, LMU Munich; Department of Neurology (M.W.G.), University of Magdeburg, University Hospital; German Center for Neurodegenerative Diseases (DZNE) (M.W.G.), Magdeburg, Germany; Stroke Center and Department of Neurology (N.P.), University Hospital Basel, Switzerland; and German Center for Neurodegenerative Diseases (DZNE) (M. Dichgans), Munich, Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
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Felix J. Bode, MD
From the Institute for Stroke and Dementia Research, University Hospital (S.T., M. Duering, A.G.K., J.B., B.G., F.A.W., M. Dichgans), and Graduate School of Systemic Neurosciences (S.T.), LMU Munich; Munich Cluster for Systems Neurology (SyNergy) (S.T., M. Dichgans), Munich, Germany; Neurologic Clinic and Policlinic (C.B., J.K.), Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Switzerland; German Center for Neurodegenerative Diseases (DZNE) (F.J.B., G.C.P.), Bonn; Department of Neurology (F.J.B., G.C.P.), University Hospital Bonn; Departments of Neurology (M.K., L.K.), Neuroradiology (F.D.), and Radiology (B.E.-W.), University Hospital, LMU Munich; Department of Neurology (M.W.G.), University of Magdeburg, University Hospital; German Center for Neurodegenerative Diseases (DZNE) (M.W.G.), Magdeburg, Germany; Stroke Center and Department of Neurology (N.P.), University Hospital Basel, Switzerland; and German Center for Neurodegenerative Diseases (DZNE) (M. Dichgans), Munich, Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
View all articles by this author
Matthias Klein, MD
From the Institute for Stroke and Dementia Research, University Hospital (S.T., M. Duering, A.G.K., J.B., B.G., F.A.W., M. Dichgans), and Graduate School of Systemic Neurosciences (S.T.), LMU Munich; Munich Cluster for Systems Neurology (SyNergy) (S.T., M. Dichgans), Munich, Germany; Neurologic Clinic and Policlinic (C.B., J.K.), Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Switzerland; German Center for Neurodegenerative Diseases (DZNE) (F.J.B., G.C.P.), Bonn; Department of Neurology (F.J.B., G.C.P.), University Hospital Bonn; Departments of Neurology (M.K., L.K.), Neuroradiology (F.D.), and Radiology (B.E.-W.), University Hospital, LMU Munich; Department of Neurology (M.W.G.), University of Magdeburg, University Hospital; German Center for Neurodegenerative Diseases (DZNE) (M.W.G.), Magdeburg, Germany; Stroke Center and Department of Neurology (N.P.), University Hospital Basel, Switzerland; and German Center for Neurodegenerative Diseases (DZNE) (M. Dichgans), Munich, Germany.
Disclosure
Scientific Advisory Boards:
1.
BioMerieux, Advisory Board, commercial, unrelated to study.
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
View all articles by this author
Franziska Dorn, MD
From the Institute for Stroke and Dementia Research, University Hospital (S.T., M. Duering, A.G.K., J.B., B.G., F.A.W., M. Dichgans), and Graduate School of Systemic Neurosciences (S.T.), LMU Munich; Munich Cluster for Systems Neurology (SyNergy) (S.T., M. Dichgans), Munich, Germany; Neurologic Clinic and Policlinic (C.B., J.K.), Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Switzerland; German Center for Neurodegenerative Diseases (DZNE) (F.J.B., G.C.P.), Bonn; Department of Neurology (F.J.B., G.C.P.), University Hospital Bonn; Departments of Neurology (M.K., L.K.), Neuroradiology (F.D.), and Radiology (B.E.-W.), University Hospital, LMU Munich; Department of Neurology (M.W.G.), University of Magdeburg, University Hospital; German Center for Neurodegenerative Diseases (DZNE) (M.W.G.), Magdeburg, Germany; Stroke Center and Department of Neurology (N.P.), University Hospital Basel, Switzerland; and German Center for Neurodegenerative Diseases (DZNE) (M. Dichgans), Munich, Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
consultant for Acandis, Germany
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
View all articles by this author
Benno Gesierich, PhD
From the Institute for Stroke and Dementia Research, University Hospital (S.T., M. Duering, A.G.K., J.B., B.G., F.A.W., M. Dichgans), and Graduate School of Systemic Neurosciences (S.T.), LMU Munich; Munich Cluster for Systems Neurology (SyNergy) (S.T., M. Dichgans), Munich, Germany; Neurologic Clinic and Policlinic (C.B., J.K.), Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Switzerland; German Center for Neurodegenerative Diseases (DZNE) (F.J.B., G.C.P.), Bonn; Department of Neurology (F.J.B., G.C.P.), University Hospital Bonn; Departments of Neurology (M.K., L.K.), Neuroradiology (F.D.), and Radiology (B.E.-W.), University Hospital, LMU Munich; Department of Neurology (M.W.G.), University of Magdeburg, University Hospital; German Center for Neurodegenerative Diseases (DZNE) (M.W.G.), Magdeburg, Germany; Stroke Center and Department of Neurology (N.P.), University Hospital Basel, Switzerland; and German Center for Neurodegenerative Diseases (DZNE) (M. Dichgans), Munich, Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
View all articles by this author
Lars Kellert, MD
From the Institute for Stroke and Dementia Research, University Hospital (S.T., M. Duering, A.G.K., J.B., B.G., F.A.W., M. Dichgans), and Graduate School of Systemic Neurosciences (S.T.), LMU Munich; Munich Cluster for Systems Neurology (SyNergy) (S.T., M. Dichgans), Munich, Germany; Neurologic Clinic and Policlinic (C.B., J.K.), Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Switzerland; German Center for Neurodegenerative Diseases (DZNE) (F.J.B., G.C.P.), Bonn; Department of Neurology (F.J.B., G.C.P.), University Hospital Bonn; Departments of Neurology (M.K., L.K.), Neuroradiology (F.D.), and Radiology (B.E.-W.), University Hospital, LMU Munich; Department of Neurology (M.W.G.), University of Magdeburg, University Hospital; German Center for Neurodegenerative Diseases (DZNE) (M.W.G.), Magdeburg, Germany; Stroke Center and Department of Neurology (N.P.), University Hospital Basel, Switzerland; and German Center for Neurodegenerative Diseases (DZNE) (M. Dichgans), Munich, Germany.
Disclosure
Scientific Advisory Boards:
1.
scientific advisory board for Boehringer Ingelheim, Bayer Vital and Daichii Sankyo
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
Travel fees from Bayer, Pfizer Vital
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
Speaker honaria from Bayer Vital, Boehringer Ingelheim, BMS, Pfizer
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
View all articles by this author
Birgit Ertl-Wagner, MD
From the Institute for Stroke and Dementia Research, University Hospital (S.T., M. Duering, A.G.K., J.B., B.G., F.A.W., M. Dichgans), and Graduate School of Systemic Neurosciences (S.T.), LMU Munich; Munich Cluster for Systems Neurology (SyNergy) (S.T., M. Dichgans), Munich, Germany; Neurologic Clinic and Policlinic (C.B., J.K.), Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Switzerland; German Center for Neurodegenerative Diseases (DZNE) (F.J.B., G.C.P.), Bonn; Department of Neurology (F.J.B., G.C.P.), University Hospital Bonn; Departments of Neurology (M.K., L.K.), Neuroradiology (F.D.), and Radiology (B.E.-W.), University Hospital, LMU Munich; Department of Neurology (M.W.G.), University of Magdeburg, University Hospital; German Center for Neurodegenerative Diseases (DZNE) (M.W.G.), Magdeburg, Germany; Stroke Center and Department of Neurology (N.P.), University Hospital Basel, Switzerland; and German Center for Neurodegenerative Diseases (DZNE) (M. Dichgans), Munich, Germany.
Disclosure
Scientific Advisory Boards:
1.
(1) Bracco Editorial Board (commercial entity) (2) Springer Medical Publisher (commercial entity)
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
(1) Bracco, travel expenses (2) Novartis, speaker honoraria, travel expenses
Editorial Boards:
1.
(1) Journal of the American College of Radiology, Associate International Editor, since 2010 (2) Radiology, Deputy Editor, since 2016
Patents:
1.
NONE
Publishing Royalties:
1.
(1) Paediatrische Neuroraiologie, Springer Medical Publisher, 2005 (2) Aerztliches Qualitaetsmanagement, Springer Medical Publisher, 2009, 2012 (3) Radiologie Trainer 3 Baende, Thieme Medical Publisher, 2005, 2012
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
(1) Munich Medical International
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
(1) Eli Lily (2) Bracco (3) Merck Serono (4) Biogen All institutional support
Research Support, Government Entities:
1.
(1) Bundesministerium fuer Forschung und Technik (2) Deutsche Forschungsgemeinschaft (3) National Institutes of Health
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
(1) Bayerische Forschungsstiftung Stock/Stock Options, Medical Equipment & Materials: (1) Siemens healthcare, stock options held by husband
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
View all articles by this author
Michael W. Goertler, MD
From the Institute for Stroke and Dementia Research, University Hospital (S.T., M. Duering, A.G.K., J.B., B.G., F.A.W., M. Dichgans), and Graduate School of Systemic Neurosciences (S.T.), LMU Munich; Munich Cluster for Systems Neurology (SyNergy) (S.T., M. Dichgans), Munich, Germany; Neurologic Clinic and Policlinic (C.B., J.K.), Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Switzerland; German Center for Neurodegenerative Diseases (DZNE) (F.J.B., G.C.P.), Bonn; Department of Neurology (F.J.B., G.C.P.), University Hospital Bonn; Departments of Neurology (M.K., L.K.), Neuroradiology (F.D.), and Radiology (B.E.-W.), University Hospital, LMU Munich; Department of Neurology (M.W.G.), University of Magdeburg, University Hospital; German Center for Neurodegenerative Diseases (DZNE) (M.W.G.), Magdeburg, Germany; Stroke Center and Department of Neurology (N.P.), University Hospital Basel, Switzerland; and German Center for Neurodegenerative Diseases (DZNE) (M. Dichgans), Munich, Germany.
Disclosure
Scientific Advisory Boards:
1.
(1)Boehringer Ingelheim GmbH
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
(1)Bayer Vital GmbH,(2)Daiichy-Sankyo Deutschland GmbH
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
View all articles by this author
Gabor C. Petzold, MD
From the Institute for Stroke and Dementia Research, University Hospital (S.T., M. Duering, A.G.K., J.B., B.G., F.A.W., M. Dichgans), and Graduate School of Systemic Neurosciences (S.T.), LMU Munich; Munich Cluster for Systems Neurology (SyNergy) (S.T., M. Dichgans), Munich, Germany; Neurologic Clinic and Policlinic (C.B., J.K.), Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Switzerland; German Center for Neurodegenerative Diseases (DZNE) (F.J.B., G.C.P.), Bonn; Department of Neurology (F.J.B., G.C.P.), University Hospital Bonn; Departments of Neurology (M.K., L.K.), Neuroradiology (F.D.), and Radiology (B.E.-W.), University Hospital, LMU Munich; Department of Neurology (M.W.G.), University of Magdeburg, University Hospital; German Center for Neurodegenerative Diseases (DZNE) (M.W.G.), Magdeburg, Germany; Stroke Center and Department of Neurology (N.P.), University Hospital Basel, Switzerland; and German Center for Neurodegenerative Diseases (DZNE) (M. Dichgans), Munich, Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
(1) Pfizer, travel honoraria (2) Boehringer, travel honoraria
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
(1) European Union (EU) JPND Program (2) German Center for Neurodegenerative Diseases (DZNE)
Research Support, Foundations and Societies:
1.
(1) Alzheimer Forschung Initiative (AFI) Germany
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
View all articles by this author
Jens Kuhle, MD
From the Institute for Stroke and Dementia Research, University Hospital (S.T., M. Duering, A.G.K., J.B., B.G., F.A.W., M. Dichgans), and Graduate School of Systemic Neurosciences (S.T.), LMU Munich; Munich Cluster for Systems Neurology (SyNergy) (S.T., M. Dichgans), Munich, Germany; Neurologic Clinic and Policlinic (C.B., J.K.), Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Switzerland; German Center for Neurodegenerative Diseases (DZNE) (F.J.B., G.C.P.), Bonn; Department of Neurology (F.J.B., G.C.P.), University Hospital Bonn; Departments of Neurology (M.K., L.K.), Neuroradiology (F.D.), and Radiology (B.E.-W.), University Hospital, LMU Munich; Department of Neurology (M.W.G.), University of Magdeburg, University Hospital; German Center for Neurodegenerative Diseases (DZNE) (M.W.G.), Magdeburg, Germany; Stroke Center and Department of Neurology (N.P.), University Hospital Basel, Switzerland; and German Center for Neurodegenerative Diseases (DZNE) (M. Dichgans), Munich, Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
JK?s institution (University Hospital Basel) received in the last 3 years and used exclusively for research support: Speaker honoraria: (1) Swiss MS Society (2) Biogen (3) Novartis (4) Roche (5) Genzyme Travel expenses: (1) Merck Serono (2) Novartis (3) Roche
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
(1) Bayer AG (2) Biogen (2) Genzyme (3) Merck (4) Novartis (5) Roche Pharma (Schweiz) AG
Research Support, Government Entities:
1.
(1) Swiss National Research Foundation
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
(1) ECTRIMS Research Fellowship Programme (2) University of Basel (3) Swiss MS Society
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
View all articles by this author
Frank A. Wollenweber, MD
From the Institute for Stroke and Dementia Research, University Hospital (S.T., M. Duering, A.G.K., J.B., B.G., F.A.W., M. Dichgans), and Graduate School of Systemic Neurosciences (S.T.), LMU Munich; Munich Cluster for Systems Neurology (SyNergy) (S.T., M. Dichgans), Munich, Germany; Neurologic Clinic and Policlinic (C.B., J.K.), Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Switzerland; German Center for Neurodegenerative Diseases (DZNE) (F.J.B., G.C.P.), Bonn; Department of Neurology (F.J.B., G.C.P.), University Hospital Bonn; Departments of Neurology (M.K., L.K.), Neuroradiology (F.D.), and Radiology (B.E.-W.), University Hospital, LMU Munich; Department of Neurology (M.W.G.), University of Magdeburg, University Hospital; German Center for Neurodegenerative Diseases (DZNE) (M.W.G.), Magdeburg, Germany; Stroke Center and Department of Neurology (N.P.), University Hospital Basel, Switzerland; and German Center for Neurodegenerative Diseases (DZNE) (M. Dichgans), Munich, Germany.
Disclosure
Scientific Advisory Boards:
1.
(1) Commercial: Served in an advisory board for Boehringer Ingelheim and Bayer.
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
Commercial: Received travel expenses from Boehringer Ingelheim. Received Honoraria for speaking engagements from BMS- Pfizer and Bayer
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
View all articles by this author
Nils Peters, MD‡
From the Institute for Stroke and Dementia Research, University Hospital (S.T., M. Duering, A.G.K., J.B., B.G., F.A.W., M. Dichgans), and Graduate School of Systemic Neurosciences (S.T.), LMU Munich; Munich Cluster for Systems Neurology (SyNergy) (S.T., M. Dichgans), Munich, Germany; Neurologic Clinic and Policlinic (C.B., J.K.), Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Switzerland; German Center for Neurodegenerative Diseases (DZNE) (F.J.B., G.C.P.), Bonn; Department of Neurology (F.J.B., G.C.P.), University Hospital Bonn; Departments of Neurology (M.K., L.K.), Neuroradiology (F.D.), and Radiology (B.E.-W.), University Hospital, LMU Munich; Department of Neurology (M.W.G.), University of Magdeburg, University Hospital; German Center for Neurodegenerative Diseases (DZNE) (M.W.G.), Magdeburg, Germany; Stroke Center and Department of Neurology (N.P.), University Hospital Basel, Switzerland; and German Center for Neurodegenerative Diseases (DZNE) (M. Dichgans), Munich, Germany.
Disclosure
Scientific Advisory Boards:
1.
Bayer Boehringer BMS/Pfizer Daiichi Sankyo
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
Boehringer
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
Schweizer Nationalfonds
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
View all articles by this author
Martin Dichgans, MD‡
From the Institute for Stroke and Dementia Research, University Hospital (S.T., M. Duering, A.G.K., J.B., B.G., F.A.W., M. Dichgans), and Graduate School of Systemic Neurosciences (S.T.), LMU Munich; Munich Cluster for Systems Neurology (SyNergy) (S.T., M. Dichgans), Munich, Germany; Neurologic Clinic and Policlinic (C.B., J.K.), Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Switzerland; German Center for Neurodegenerative Diseases (DZNE) (F.J.B., G.C.P.), Bonn; Department of Neurology (F.J.B., G.C.P.), University Hospital Bonn; Departments of Neurology (M.K., L.K.), Neuroradiology (F.D.), and Radiology (B.E.-W.), University Hospital, LMU Munich; Department of Neurology (M.W.G.), University of Magdeburg, University Hospital; German Center for Neurodegenerative Diseases (DZNE) (M.W.G.), Magdeburg, Germany; Stroke Center and Department of Neurology (N.P.), University Hospital Basel, Switzerland; and German Center for Neurodegenerative Diseases (DZNE) (M. Dichgans), Munich, Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
(1) Bayer Vital, funding for travel to speak (2) Boehringer Ingelheim,funding for travel to speak (3) Daiichi-Sankyo,funding for travel to speak (4) 4SC Discovery GmbH,funding for travel to speak (5) Pfizer Pharma GmbH,funding for travel to speak
Editorial Boards:
1.
(1) Stroke the International Journal of Stroke, Section Editor Stroke (AHA) 2006 - 2010 and 2015- present, (2) Genetics Intern. J. Stroke, Section Editor, 2013-2016 (WSO) (3) Journal of Neurochemistry, Handling Editor, 2011-2016 (4) Frontiers in Stroke, Associate Editor, 2010- present (5) Annals of Neurology, Editorial Board Member, 2017- present (6) European Stroke Journal, Editor, 2016- present
Patents:
1.
NONE
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(1) Bayer Vital, (2) Boehringer Ingelheim, (3)4SC Discovery GmbH, (4) Daiichi Sankyo (5) EVER Neuro Pharma
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(1)European Union (EU-Horizon 2020,GA No. 667375),PI, 12/2015-11/2020 (2) European Union (EU-Horizon 2020,GA No. 666881) Coordinator, 01/2016-12/2020 (3) German Federal Ministry of Education and Research (BMBF), principal investigator,01ZX1313F,12/13-11/16 (4) DFG, EXC 1010/1, principal investigator, 01/2013- 12/2018 (5) DFG, SFB 1123/1, B03, principal investigator, 10/2014- 07/2022 (6) DFG, GZ: DI 722/13-1, principal investigator, 01/2017- 12/2019 (7) Fondation Leducq, Grant no.12 CVD 01, principal investigator, 10/2012-09/2018
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(1) Vascular Dementia Research Foundation
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Notes

Correspondence Dr. Dichgans [email protected]
*
These authors contributed equally to this work.
‡
These authors contributed equally to this work.
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

Author Contributions

Steffen Tiedt, MD: conception and design of the study, acquisition, analysis, and interpretation of data, drafting a significant portion of the manuscript or figures. Marco Duering, MD: conception and design of the study, acquisition, analysis, and interpretation of data, drafting a significant portion of the manuscript or figures. Christian Barro, MD: acquisition, analysis, and interpretation of data. Asli Gizem Kaya: acquisition, analysis, and interpretation of data. Julia Boeck: acquisition, analysis, and interpretation of data. Felix J. Bode, MD: acquisition, analysis, and interpretation of data. Matthias Klein, MD: acquisition, analysis, and interpretation of data. Franziska Dorn, MD: acquisition, analysis, and interpretation of data. Benno Gesierich, PhD: acquisition, analysis, and interpretation of data. Lars Kellert, MD: acquisition, analysis, and interpretation of data. Birgit Ertl-Wagner, MD: acquisition, analysis, and interpretation of data. Michael W. Goertler, MD: acquisition, analysis, and interpretation of data. Gabor C. Petzold, MD: acquisition, analysis, and interpretation of data. Jens Kuhle, MD: acquisition, analysis, and interpretation of data. Frank A. Wollenweber, MD: conception and design of the study, acquisition, analysis, and interpretation of data. Nils Peters, MD: conception and design of the study, acquisition, analysis, and interpretation of data. Martin Dichgans, MD: conception and design of the study, drafting a significant portion of the manuscript or figures.

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