Multicenter Study

. 2021 Jun 7;12(1):3400.

doi: 10.1038/s41467-021-23620-z.

A multicentre validation study of the diagnostic value of plasma neurofilament light

Nicholas J Ashton^{1

2

3

4}, Shorena Janelidze⁵, Ahmad Al Khleifat⁶, Antoine Leuzy⁵, Emma L van der Ende⁷, Thomas K Karikari⁸, Andrea L Benedet^{9

10}, Tharick A Pascoal^{9

10}, Alberto Lleó^{11

12}, Lucilla Parnetti¹³, Daniela Galimberti^{14

15}, Laura Bonanni¹⁶, Andrea Pilotto^{17

18}, Alessandro Padovani¹⁷, Jan Lycke^{19

20}, Lenka Novakova^{19

20}, Markus Axelsson^{19

20}, Latha Velayudhan^{21

22}, Gil D Rabinovici^{23

24}, Bruce Miller²³, Carmine Pariante²⁵, Naghmeh Nikkheslat²⁵, Susan M Resnick²⁶, Madhav Thambisetty²⁷, Michael Schöll^{8

28

29}, Gorka Fernández-Eulate^{30

31}, Francisco J Gil-Bea^{30

32}, Adolfo López de Munain^{30

31

32

33}, Ammar Al-Chalabi^{6

34}, Pedro Rosa-Neto^{9

10}, Andre Strydom^{35

36

37}, Per Svenningsson^{21

38}, Erik Stomrud^{5

39}, Alexander Santillo⁵, Dag Aarsland^{21

40

41}, John C van Swieten⁷, Sebastian Palmqvist^{5

42}, Henrik Zetterberg^{8

29

43

44}, Kaj Blennow^{8

43}, Abdul Hye^{21

40

41}, Oskar Hansson^{45

46}

Affiliations

¹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden. nicholas.ashton@gu.se.
² Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden. nicholas.ashton@gu.se.
³ Department of Old Age Psychiatry, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK. nicholas.ashton@gu.se.
⁴ NIHR Biomedical Research Centre for Mental Health & Biomedical Research Unit for Dementia at South London & Maudsley NHS Foundation, London, UK. nicholas.ashton@gu.se.
⁵ Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden.
⁶ Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.
⁷ Department of Neurology and Alzheimer Center, Erasmus University Medical Center, Rotterdam, Netherlands.
⁸ Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
⁹ Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Montreal, QC, Canada.
¹⁰ Montreal Neurological Institute, Montreal, QC, Canada.
¹¹ Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
¹² CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain.
¹³ Laboratory of Clinical Neurochemistry, Neurology Clinic, University of Perugia, Perugia, Italy.
¹⁴ Fondazione IRCCS Ca' Granda, Ospedale Policlinico, Milan, Italy.
¹⁵ Dino Ferrari Center, University of Milan, Milan, Italy.
¹⁶ Department of Neuroscience, Imaging and Clinical Sciences, University G.d'Annunzio of Chieti-Pescara, Chieti, Italy.
¹⁷ Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
¹⁸ Parkinson's Disease Rehabilitation Centre, FERB ONLUS, Trescore Balneario, BG, Italy.
¹⁹ Department of Clinical Neuroscience, Institution of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
²⁰ Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden.
²¹ Department of Old Age Psychiatry, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.
²² Department of Health Sciences, University of Leicester, Leicester, UK.
²³ Department of Neurology, University of California San Francisco, Memory and Aging Center, San Francisco, CA, USA.
²⁴ Department of Radiology & Biomedical Imaging, University of California, San Francisco, CA, USA.
²⁵ Stress, Psychiatry and Immunology Lab & Perinatal Psychiatry, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.
²⁶ Brain Aging and Behavior Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
²⁷ Clinical and Translational Neuroscience Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
²⁸ Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.
²⁹ Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London, UK.
³⁰ Neurosciences Area, Biodonostia Health Research Institute, San Sebastián, Spain.
³¹ Department of Neurology, Donostia University Hospital, Osakidetza, San Sebastián, Spain.
³² CIBERNED, Carlos III Health Institute, Madrid, Spain.
³³ Department of Neurosciences, Basque Country University, San Sebastián, Spain.
³⁴ Department of Neurology, King's College Hospital, London, UK.
³⁵ Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
³⁶ South London and Maudsley NHS Foundation Trust, London, UK.
³⁷ London Down Syndrome Consortium (LonDowns), London, UK.
³⁸ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
³⁹ Memory Clinic, Skåne University Hospital, Malmö, Sweden.
⁴⁰ NIHR Biomedical Research Centre for Mental Health & Biomedical Research Unit for Dementia at South London & Maudsley NHS Foundation, London, UK.
⁴¹ Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
⁴² Department of Neurology, Skåne University Hospital, Lund University, Lund, Sweden.
⁴³ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁴⁴ UK Dementia Research Institute, University College London, London, UK.
⁴⁵ Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden. oskar.hansson@med.lu.se.
⁴⁶ Memory Clinic, Skåne University Hospital, Malmö, Sweden. oskar.hansson@med.lu.se.

PMID: 34099648
PMCID: PMC8185001
DOI: 10.1038/s41467-021-23620-z

Multicenter Study

A multicentre validation study of the diagnostic value of plasma neurofilament light

Nicholas J Ashton et al. Nat Commun. 2021.

. 2021 Jun 7;12(1):3400.

doi: 10.1038/s41467-021-23620-z.

Authors

Affiliations

¹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden. nicholas.ashton@gu.se.
² Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden. nicholas.ashton@gu.se.
³ Department of Old Age Psychiatry, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK. nicholas.ashton@gu.se.
⁴ NIHR Biomedical Research Centre for Mental Health & Biomedical Research Unit for Dementia at South London & Maudsley NHS Foundation, London, UK. nicholas.ashton@gu.se.
⁵ Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden.
⁶ Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.
⁷ Department of Neurology and Alzheimer Center, Erasmus University Medical Center, Rotterdam, Netherlands.
⁸ Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
⁹ Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Montreal, QC, Canada.
¹⁰ Montreal Neurological Institute, Montreal, QC, Canada.
¹¹ Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
¹² CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain.
¹³ Laboratory of Clinical Neurochemistry, Neurology Clinic, University of Perugia, Perugia, Italy.
¹⁴ Fondazione IRCCS Ca' Granda, Ospedale Policlinico, Milan, Italy.
¹⁵ Dino Ferrari Center, University of Milan, Milan, Italy.
¹⁶ Department of Neuroscience, Imaging and Clinical Sciences, University G.d'Annunzio of Chieti-Pescara, Chieti, Italy.
¹⁷ Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
¹⁸ Parkinson's Disease Rehabilitation Centre, FERB ONLUS, Trescore Balneario, BG, Italy.
¹⁹ Department of Clinical Neuroscience, Institution of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
²⁰ Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden.
²¹ Department of Old Age Psychiatry, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.
²² Department of Health Sciences, University of Leicester, Leicester, UK.
²³ Department of Neurology, University of California San Francisco, Memory and Aging Center, San Francisco, CA, USA.
²⁴ Department of Radiology & Biomedical Imaging, University of California, San Francisco, CA, USA.
²⁵ Stress, Psychiatry and Immunology Lab & Perinatal Psychiatry, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.
²⁶ Brain Aging and Behavior Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
²⁷ Clinical and Translational Neuroscience Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
²⁸ Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.
²⁹ Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London, UK.
³⁰ Neurosciences Area, Biodonostia Health Research Institute, San Sebastián, Spain.
³¹ Department of Neurology, Donostia University Hospital, Osakidetza, San Sebastián, Spain.
³² CIBERNED, Carlos III Health Institute, Madrid, Spain.
³³ Department of Neurosciences, Basque Country University, San Sebastián, Spain.
³⁴ Department of Neurology, King's College Hospital, London, UK.
³⁵ Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
³⁶ South London and Maudsley NHS Foundation Trust, London, UK.
³⁷ London Down Syndrome Consortium (LonDowns), London, UK.
³⁸ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
³⁹ Memory Clinic, Skåne University Hospital, Malmö, Sweden.
⁴⁰ NIHR Biomedical Research Centre for Mental Health & Biomedical Research Unit for Dementia at South London & Maudsley NHS Foundation, London, UK.
⁴¹ Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
⁴² Department of Neurology, Skåne University Hospital, Lund University, Lund, Sweden.
⁴³ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁴⁴ UK Dementia Research Institute, University College London, London, UK.
⁴⁵ Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden. oskar.hansson@med.lu.se.
⁴⁶ Memory Clinic, Skåne University Hospital, Malmö, Sweden. oskar.hansson@med.lu.se.

PMID: 34099648
PMCID: PMC8185001
DOI: 10.1038/s41467-021-23620-z

Abstract

Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King's College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.

PubMed Disclaimer

Conflict of interest statement

J.L. has received travel support and/or lecture honoraria from Biogen, Novartis, Merck, Roche, and Sanofi Genzyme; has served on scientific advisory boards for Biogen, Novartis, Merck, Alexion, Roche, and Sanofi Genzyme; serves on the editorial board of the Acta Neurologica Scandinavica; has received unconditional research grants from Biogen and Novartis. A.A.C. has served as a consultant or on advisory boards for Amylyx, Apellis, Biogen Idec, Brainstorm, Cytokinetics, GSK, Lilly, Mitsubishi Tanabe Pharma, Novartis, OrionPharma, Quralis, and Wave Pharmaceuticals. A.S. has been a consultant for AC-Immune and is a member of the scientific advisory board of ProMIS Neurosciences. P.S. has received speaker fees for Shire/Takeda and Sanofi Genzyme. H.Z. has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, and CogRx; has given lectures in symposia sponsored by Alzecure and Biogen; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. K.B. has served as a consultant or at advisory boards for Alector, Alzheon, CogRx, Biogen, Lilly, Novartis, and Roche Diagnostics, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Venture-based platform company at the University of Gothenburg, all unrelated to the work presented in this paper. O.H. has acquired research support (for the institution) from Roche, GE Healthcare, Biogen, AVID Radiopharmaceuticals, and Euroimmun. In the past 2 years, he has received consultancy/speaker fees (paid to the institution) from Biogen and Roche. The remaining authors declare no competing interests.

Figures

**Fig. 1. The concentrations of plasma NfL for different diagnostic and controls groups in the KCL and Lund cohorts.**
Plasma neurofilament light (NfL) in different diagnostic groups; KCL (A n = 805) and Lund (B n = 1464) cohorts. For each plot, the horizontal bar shows the median, and the upper and lower boundaries show the 25th and 75th percentiles, respectively. Source data are provided as a Source Data file. KCL Cohort—AD Alzheimer’s disease (n = 102), ALS amyotrophic lateral sclerosis (n = 50), CU Aβ− cognitively unimpaired without Aβ pathology (n = 130), CU Aβ+ cognitively unimpaired with Aβ pathology (n = 28), CBS/PSP corticobasal syndrome and progressive supranuclear palsy (n = 19), depression (n = 37), DS Down syndrome (n = 29), DSAD Down syndrome Alzheimer’s disease (n = 12), EOAD early-onset Alzheimer’s disease (n = 59), FTD frontotemporal dementia (n = 54), MCI Aβ− mild cognitive impairment without Aβ pathology (n = 55), MCI Aβ+ mild cognitive impairment with Aβ pathology (n = 31), PD Parkinson’s disease (n = 140), PDD/DLB Parkinson’s disease dementia and dementia with Lewy bodies (n = 59). Lund Cohort—AD Alzheimer’s disease (n = 134), CU Aβ− cognitively unimpaired without Aβ pathology (n = 273), CU Aβ+ cognitively unimpaired with Aβ pathology (n = 103), CBS/PSP corticobasal syndrome and progressive supranuclear palsy (n = 24), EOAD early-onset Alzheimer’s disease (n = 23), FTD frontotemporal dementia (n = 150), MCI Aβ− mild cognitive impairment without Aβ pathology (n = 115), MCI Aβ+ mild cognitive impairment with Aβ pathology (n = 165), MSA multiple system atrophy (n = 29), PD Parkinson’s disease (n = 171), PDD/DLB Parkinson’s disease dementia and dementia with Lewy bodies (n = 46), SCD Aβ− subjective cognitive decline without Aβ pathology (n = 134), SCD Aβ+ subjective cognitive decline with Aβ pathology (n = 75), VaD vascular dementia (n = 22).

**Fig. 2. Effect sizes of neurodegenerative disorders as compared to amyloid-negative cognitively unimpaired controls, Parkinson’s disease and Alzheimer’s disease.**
Effect sizes (Hedges’s g) of different neurodegenerative disorders as compared to amyloid-negative cognitively unimpaired controls (A n = 403), Parkinson’s disease (B n = 311), and Alzheimer’s disease (C n = 236). The bars represent the mean effect size for the cohort, whereas the error bars represent the standard deviation of effect size when considering the KCL and Lund cohorts separately. Those without error bars (e.g., VaD) are only included in one cohort. AD Alzheimer’s disease (n = 236), ALS amyotrophic lateral sclerosis (n = 50), CU Aβ− cognitively unimpaired without Aβ pathology (n = 403), CBS/PSP corticobasal syndrome and progressive supranuclear palsy (n = 43), depression (n = 37), DS Down syndrome (n = 29), DSAD Down syndrome Alzheimer’s disease (n = 12), EOAD early-onset Alzheimer’s disease (n = 82), FTD frontotemporal dementia (n = 204), MCI Aβ− mild cognitive impairment without Aβ pathology (n = 170), MCI Aβ + mild cognitive impairment with Aβ pathology (n = 196), MSA multiple system atrophy (n = 29), PD Parkinson’s disease (n = 311), PDD/DLB Parkinson’s disease dementia and dementia with Lewy bodies (n = 105), VaD vascular dementia (n = 22).

**Fig. 3. The diagnsotic accuracy of plasma NfL in neurodegenerative disorders.**
Heatmaps to demonstrate the accuracy (AUC) of plasma NfL to distinguish CU and neurodegenerative disorders in the KCL (A) and Lund (B) cohorts. Heatmaps tables that demonstrate sensitivity, specificity, and 95% CI of AUC displayed in the Supplementary Tables 4–5 and Supplementary Fig. 4. AD Alzheimer’s disease, ALS amyotrophic lateral sclerosis, CU Aβ− cognitively unimpaired without Aβ pathology, CU Aβ+ cognitively unimpaired with Aβ pathology, CBS/PSP corticobasal syndrome and progressive supranuclear palsy, DS Down syndrome, DSAD Down syndrome Alzheimer’s disease, EOAD early-onset Alzheimer’s disease, FTD frontotemporal dementia, MCI Aβ− mild cognitive impairment without Aβ pathology, MCI Aβ+ mild cognitive impairment with Aβ pathology, MSA multiple system atrophy, PD Parkinson’s disease, PDD/DLB Parkinson’s disease dementia and dementia with Lewy bodies, SCD Aβ− subjective cognitive decline without Aβ pathology, SCD Aβ+ subjective cognitive decline with Aβ pathology, VaD vascular dementia.

**Fig. 4. The diagnsotic accuracy of plasma NfL in identifying neurodegenerative disorders from controls (young/old) and depression.**
The performance of plasma neurofilament light (NfL) to identify neurodegenerative disorders from controls (CU and SCD) > 65 years of age (A), controls (CU and SCD) < 65 years of age (B), and depression (C).

**Fig. 5. The performance of plasma NfL concentration cutoffs to identify neurodegenerative disorders of all ages.**
The performance of plasma neurofilament light (NfL) concentration cutoffs to identify neurodegenerative disorders in KCL (A) and Lund (B). AD Alzheimer’s disease, ALS amyotrophic lateral sclerosis, CBS corticobasal syndrome, DLB dementia with Lewy bodies, DS Down syndrome, DSAD Down syndrome Alzheimer’s disease, EOAD early-onset Alzheimer’s disease, FTD frontotemporal dementia. MCI mild cognitive impairment, MSA multiple system atrophy, PD Parkinson’s disease, PDD Parkinson’s disease dementia, PSP progressive supranuclear palsy, SCD subjective cognitive decline, VaD vascular dementia.

**Fig. 6. The performance of plasma NfL concentration cutoffs to identify neurodegenerative disorders in >65 and <65 years.**
The performance of plasma neurofilament light (NfL) concentration cutoffs to identify neurodegenerative disorders in >65 (A) and <65 (B). The KCL and Lund cohorts are combined for this analysis. AD Alzheimer’s disease, ALS amyotrophic lateral sclerosis, CBS corticobasal syndrome, DLB dementia with Lewy bodies, DS Down syndrome, DSAD Down syndrome Alzheimer’s disease, EOAD early-onset Alzheimer’s disease, FTD frontotemporal dementia. MCI mild cognitive impairment, MSA multiple system atrophy, PD Parkinson’s disease, PDD Parkinson’s disease dementia, PSP progressive supranuclear palsy, SCD subjective cognitive decline, VaD vascular dementia.

See this image and copyright information in PMC

References

1. Blennow K, Zetterberg H. Biomarkers for Alzheimer’s disease: current status and prospects for the future. J. Intern. Med. 2018;284:643–663. doi: 10.1111/joim.12816. - DOI - PubMed
1. Jack CR, Jr., et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14:535–562. doi: 10.1016/j.jalz.2018.02.018. - DOI - PMC - PubMed
1. Khalil M, et al. Neurofilaments as biomarkers in neurological disorders. Nat. Rev. Neurol. 2018;14:577–589. doi: 10.1038/s41582-018-0058-z. - DOI - PubMed
1. Olsson B, et al. Association of cerebrospinal fluid neurofilament light protein levels with cognition in patients with dementia, motor neuron disease, and movement disorders. JAMA Neurol. 2019;76:318–325. doi: 10.1001/jamaneurol.2018.3746. - DOI - PMC - PubMed
1. Novakova L, et al. Monitoring disease activity in multiple sclerosis using serum neurofilament light protein. Neurology. 2017;89:2230–2237. doi: 10.1212/WNL.0000000000004683. - DOI - PMC - PubMed

Publication types

Actions
Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

A multicentre validation study of the diagnostic value of plasma neurofilament light

Affiliations

A multicentre validation study of the diagnostic value of plasma neurofilament light

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical