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Neurodegeneration
Original research
Serum GFAP differentiates Alzheimer’s disease from frontotemporal dementia and predicts MCI-to-dementia conversion
  1. Patrick Oeckl1,2,
  2. Sarah Anderl-Straub1,
  3. Christine A F Von Arnim1,3,
  4. Inês Baldeiras4,5,
  5. Janine Diehl-Schmid6,
  6. Timo Grimmer6,
  7. Steffen Halbgebauer1,
  8. Anna M Kort7,
  9. Marisa Lima4,
  10. Tainá M Marques7,8,
  11. Marion Ortner6,
  12. Isabel Santana4,5,
  13. Petra Steinacker1,
  14. Marcel M Verbeek7,8,
  15. Alexander E Volk9,
  16. Albert C Ludolph1,2,
  17. Markus Otto1,10
  1. 1Department of Neurology, Ulm University, Ulm, Germany
  2. 2German Center for Neurodegenerative Diseases (DZNE e.V.), Ulm, Germany
  3. 3Division of Geriatrics, University Medical Center Göttingen, Göttingen, Niedersachsen, Germany
  4. 4Center for Neurosciences and Cell Biology-CIBB, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
  5. 5Centro Hospitalar de Coimbra, Coimbra, Portugal
  6. 6Department of Psychiatry and Psychotherapy, Technical University of Munich, School of Medicine, Munich, Germany
  7. 7Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Raboud Alzheimer Center, Radboud University Medical Center, Nijmegen, The Netherlands
  8. 8Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
  9. 9Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  10. 10Department of Neurology, Martin-Luther-University Halle-Wittenberg, Halle, Sachsen-Anhalt, Germany
  1. Correspondence to Professor Markus Otto, Department of Neurology, Ulm University, Ulm, Baden-Württemberg, Germany; markus.otto{at}uk-halle.de

Abstract

Objective Reactive astrogliosis is a hallmark of Alzheimer’s disease (AD) and frontotemporal dementia (FTD) but differences between the diseases and time course are unclear. Here, we used serum levels of the astroglial marker glial fibrillary acidic protein (GFAP) to investigate differences in patients with AD dementia, mild cognitive impairment (MCI)-AD and behavioural variant FTD (bvFTD).

Methods This multicentre study included serum samples from patients diagnosed with AD dementia (n=230), MCI-AD (n=111), bvFTD (n=140) and controls (n=129). A subgroup of patients with MCI-AD (n=32) was longitudinally followed-up for 3.9±2.6 years after sample collection. Serum levels of GFAP, neurofilament light chain (NfL) and pTau181 were measured by Simoa (Quanterix) and Ella (ProteinSimple).

Results In total, samples from 610 individuals from four clinical centres were investigated in this study. Serum GFAP levels in AD dementia were increased (median 375 pg/mL, IQR 276–505 pg/mL) compared with controls (167 pg/mL, IQR 108–234 pg/mL) and bvFTD (190 pg/mL, IQR 134–298 pg/mL, p<0.001). GFAP was already increased in the early disease phase (MCI-AD, 300 pg/mL, IQR 232–433 pg/mL, p<0.001) and was higher in patients with MCI-AD who developed dementia during follow-up (360 pg/mL, IQR 253–414 pg/mL vs 215 pg/mL, IQR 111–266 pg/mL, p<0.01, area under the curve (AUC)=0.77). Diagnostic performance of serum GFAP for AD (AUC=0.84, sensitivity 98%, specificity 60%, likelihood ratio 2.5) was comparable to serum pTau181 (AUC=0.89, sensitivity 80%, specificity 87%, likelihood ratio 6.0) but superior to serum NfL (AUC=0.71, sensitivity 92%, specificity 49%, likelihood ratio 1.8).

Conclusions Our data indicate a different type of reactive astrogliosis in AD and bvFTD and support serum GFAP as biomarker for differential diagnosis and prediction of MCI-to-dementia conversion.

  • frontotemporal dementia
  • Alzheimer's disease
  • clinical neurology
  • dementia

Data availability statement

Data are available on reasonable request.

https://doi.org/10.1136/jnnp-2021-328547

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    Data availability statement

    Data are available on reasonable request.

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    • Contributors Conception and design of the work: PO, Markus Otto (MO); acquisition and analysis of data: PO, SA-S, CAFVA, IB, JD-S, TG, AMK, ML, TMM, Marion Ortner (MOr), IS, MMV, AEV, MO; interpretation of data: PO, SA-S, CAFVA, IB, JD-S, TG, SH, AMK, ML, TMM, MOr, IS, PS, MMV, AEV, ACL, MO; drafting of the work: PO, MO. All authors revised the manuscript critically, approved the final version of the manuscript for publication and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. MO is responsible for the overall content as guarantor.

    • Funding The study was supported by the German Federal Ministry of Education and Research (FTLDc 01GI1007A), the German Research Foundation/DFG (SFB1279), the foundation of the state Baden-Württemberg (D.3830) and Boehringer Ingelheim Ulm University BioCenter (D.5009).

    • Disclaimer Funding sources were not involved in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript and decision to submit the manuscript for publication.

    • Competing interests PO received research support from the Michael J. Fox Foundation for Parkinsons Research (Grant ID: MJFF-010349) and Alzheimer Forschung Initiative e.V. (20059CB). CAFVA received research support from Roche Diagnostics, personal speaker honoraria from Biogen, Roche Diagnostics and Dr Willmar Schwabe GmbH & Co. KG, personal funding for attending meetings and travel from Biogen and Roche Diagnostics and personal fees for the scientific advisory boards of Biogen, Roche and Dr Willmar Schwabe GmbH & Co. KG. IB received a contract with Sanofi/Genzyme, a grant by Grupo de estudos e Envelhecimento Cerebral and payment for scientific lecturers by Merck. JD-S received funding from German Ministry of Research and Education, consulting fee by Pfizer and speaker fee by Roche. TG received grants to institution from Actelion and Novartis, consulting fees from AbbVie, Anavex, Biogen, Bracket, Eli Lilly, Functional Neuromodulation, Iqvia/Quintiles, Novartis, Novo Nordisk, NuiCare, Roche Pharma, Toyama and Vivoryon and lecture fees from Actelion, B. Braun, Biogen, Eli Lilly, Life Molecular Imaging, Novartis, Parexel and Roche Pharma. IS received personal grants from webinars promoted by pharma, personal consulting fees as member of national Ethics Committee, personal payments for presentations, personal fees for advisory board of pharma. MMV is supported by the BIONIC project (no. 733050822, which has been made possible by ZonMW within the framework of Memorabel, the research and innovation programme for dementia, as part of the Dutch national Deltaplan for Dementia: zonmw.nl/dementiaresearch), the CAFC project (the National Institutes of Health, USA, grant number 5R01NS104147-02) and by a grant from the Selfridges Group Foundation. ACL received funding from the state Baden-Württemberg, Payments were made to me 2018: Desitin 2019: Desitin Roche Teva Biogen Novartis Pharma 2020: Biogen Roche Pharma Biologix 2021: Biogen Roche Pharma Alector Neuroforum Springer. Payments for expert witness at courts/insurances. Payments from Advisory Boards, President German Society for Neurosciences, Scientific Board German Society for Neuromuscle Disease, Thierry Latran Foundation. MO received consulting fees from Axon, Biogen and Roche. SA-S, SH, AMK, ML, TMM, MOr, PS and AEV report no conflict of interest.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.