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Comparison of CSF and plasma NfL and pNfH for Alzheimer’s disease diagnosis: a memory clinic study

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Abstract

Plasma neurofilament light chain (NfL) is a promising biomarker of axonal damage for the diagnosis of neurodegenerative diseases. Phosphorylated neurofilament heavy chain (pNfH) has demonstrated its value in motor neuron diseases diagnosis, but has less been explored for dementia diagnosis. In a cross-sectional study, we compared cerebrospinal fluid (CSF) and plasma NfL and pNfH levels in n = 188 patients from Lariboisière Hospital, Paris, France, including AD patients at mild cognitive impairment stage (AD-MCI, n = 36) and dementia stage (n = 64), non-AD MCI (n = 38), non-AD dementia (n = 28) patients and control subjects (n = 22). Plasma NfL, plasma and CSF pNfH levels were measured using Simoa and CSF NfL using ELISA. The correlation between CSF and plasma levels was stronger for NfL than pNfH (rho = 0.77 and rho = 0.52, respectively). All neurofilament markers were increased in AD-MCI, AD dementia and non-AD dementia groups compared with controls. CSF NfL, CSF pNfH and plasma NfL showed high performance to discriminate AD at both MCI and dementia stages from control subjects [AUC (area under the curve) = 0.82–0.91]. Plasma pNfH displayed overall lower AUCs for discrimination between groups compared with CSF pNfH. Neurofilament markers showed similar moderate association with cognition. NfL levels displayed significant association with mediotemporal lobe atrophy and white matter lesions in the AD group. Our results suggest that CSF NfL and pNfH as well as plasma NfL levels display equivalent performance in both positive and differential AD diagnosis in memory clinic settings. In contrast to motoneuron disorders, plasma pNfH did not demonstrate added value as compared with plasma NfL.

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Data availability

Anonymized data can be shared by request from qualified investigators; providing data transfer is in agreement with EU legislation and decisions by the institutional review board of Lariboisière Hospital, APHP, Paris, France.

Abbreviations

AD:

Alzheimer’s disease

Aβ:

Amyloid beta

ALS:

Amyotrophic lateral sclerosis

AUC:

Area under the curve

CSF:

Cerebrospinal fluid

FTD:

Frontotemporal dementia

DLB:

Dementia with Lewy bodies

MMSE:

Mini-mental state examination

NfL:

Neurofilament light chain

NC:

Neurological controls

Nf:

Neurofilament

MCI:

Mild cognitive impairment

MRI:

Magnetic resonance imaging

PET:

Positron emission tomography

pNfH:

Phosphorylated neurofilament heavy chain

ROC:

Receiver operator characteristic

Simoa:

Single molecule array

VaD:

Vascular dementia

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Acknowledgements

The authors wish to sincerely thank all the patients who participated in this study and their relatives.

Funding

AV is funded by Fondation Ophtalmologique Adolphe de Rothschild, Fondation Philipe Chatrier, Amicale des Anciens Internes des Hôpitaux de Paris, Fondation Vaincre Alzheimer, the Swedish Dementia Foundation (Demensfonden), Gun and Bertil Stohnes Foundation and Gamla Tjänarinnor Foundation. NJA is funded by the Wallenberg Centre for Molecular and Translational Medicine, Swedish Alzheimer Foundation (Alzheimerfonden), the Swedish Dementia Foundation (Demensfonden), Hjärnfonden (#FO2020-0241) and Gamla Tjänarinnor. TKK was funded by the BrightFocus Foundation (#A2020812F), the International Society for Neurochemistry’s Career Development Grant, the Swedish Alzheimer Foundation (Alzheimerfonden; #AF-940244), the Swedish Brain Foundation (Hjärnfonden; #FO2021-0298), the Swedish Dementia Foundation (Demensförbundet), the Swedish Parkinson Foundation (Parkinsonfonden), Gamla Tjänarinnor Foundation, the Aina (Ann) Wallströms and Mary-Ann Sjöbloms Foundation, the Agneta Prytz-Folkes & Gösta Folkes Foundation (#2020-00124), the Gun and Bertil Stohnes Foundation, and the Anna Lisa and Brother Björnsson’s Foundation. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019-0228), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL.

Author information

Author notes

  1. Kaj Blennow and Claire Paquet are equal co-senior authors on this work.

Authors and Affiliations

  1. Cognitive Neurology Center, Lariboisière Fernand Widal Hospital, Assistance Publique Hôpitaux de Paris, Université Paris Cité, Paris, France

    Agathe Vrillon, Emmanuel Cognat, Julien Dumurgier, Matthieu Lilamand & Claire Paquet

  2. INSERM U1144, Therapeutic Optimization in Neuropsychopharmacology, Paris, France

    Agathe Vrillon, Karl Götze, Emmanuel Cognat & Claire Paquet

  3. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden

    Nicholas J. Ashton, Thomas K. Karikari, Henrik Zetterberg & Kaj Blennow

  4. Maurice Wohl Institute Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

    Nicholas J. Ashton & Henrik Zetterberg

  5. NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK

    Nicholas J. Ashton

  6. Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway

    Nicholas J. Ashton

  7. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

    Thomas K. Karikari

  8. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden

    Henrik Zetterberg & Kaj Blennow

  9. UK Dementia Research Institute at UCL, London, UK

    Henrik Zetterberg

  10. Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China

    Henrik Zetterberg

  11. Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA

    Henrik Zetterberg

Authors
  1. Agathe Vrillon
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  2. Nicholas J. Ashton
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  3. Thomas K. Karikari
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  4. Karl Götze
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  5. Emmanuel Cognat
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  6. Julien Dumurgier
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  7. Matthieu Lilamand
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  8. Henrik Zetterberg
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  9. Kaj Blennow
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  10. Claire Paquet
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Contributions

AV: acquisition of data, drafting/revision of the manuscript for content, including medical writing for content, study concept or design, analysis or interpretation of data. NJA: acquisition of data, drafting/revision of the manuscript for content, study concept or design, analysis or interpretation of data. TKK: drafting/revision of the manuscript for content, study concept or design, analysis or interpretation of data. KG: acquisition of data, drafting/revision of the manuscript for content. JD: acquisition of data, drafting/revision of the manuscript for content. EC: acquisition of data, drafting/revision of the manuscript for content ML: acquisition of data, drafting/revision of the manuscript for content. HZ: drafting/revision of the manuscript for content, study concept or design. KB: drafting/revision of the manuscript for content, study concept or design, analysis or interpretation of data. CP: acquisition of data, drafting/revision of the manuscript for content, study concept or design, analysis or interpretation of data.

Corresponding author

Correspondence to Agathe Vrillon.

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Conflicts of interest

HZ has served at scientific advisory boards for Alector, Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies and CogRx, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). CP is a member of the International Advisory Boards of Lilly; is a consultant for Fujiribio, Alzhois, Neuroimmune, Ads Neuroscience, Roche, AgenT and Gilead; and is involved as an investigator in several clinical trials for Roche, Esai, Lilly, Biogen, Astra-Zeneca, Lundbeck, and Neuroimmune. KB has served as a consultant and at advisory boards for Acumen, ALZPath, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Progra (outside submitted work).

Ethical approval

This research study was approved by the local ethics committee of Bichat Hospital, Paris, France (CEERB GHU Nord no.10-037).

Patient consent

Informed consent was obtained from the patients who participated in the study.

Supplementary Information

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Supplementary file1 (DOCX 238 KB)

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Vrillon, A., Ashton, N.J., Karikari, T.K. et al. Comparison of CSF and plasma NfL and pNfH for Alzheimer’s disease diagnosis: a memory clinic study. J Neurol 271, 1297–1310 (2024). https://doi.org/10.1007/s00415-023-12066-6

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  • DOI: https://doi.org/10.1007/s00415-023-12066-6

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