Plasma and CSF neurofilament light chain distinguish neurodegenerative from primary psychiatric conditions in a clinical setting

Dhamidhu Eratne^{1

2

3}, Matthew J Y Kang^{1

2}, Courtney Lewis^{1

2

4}, Christa Dang^{5

6}, Charles B Malpas^{7

8}, Michael Keem^{9

10

11

12}, Jasleen Grewal¹³, Vladimir Marinov¹, Amy Coe⁶, Cath Kaylor-Hughes⁶, Thomas Borchard¹⁴, Chhoa Keng-Hong^{1

15}, Alexandra Waxmann¹, Burcu Saglam¹, Tomas Kalincik^{16

17}, Richard Kanaan¹⁸, Wendy Kelso¹, Andrew Evans¹, Sarah Farrand¹, Samantha Loi^{1

2}, Mark Walterfang^{1

2}, Christiane Stehmann³, Qiao-Xin Li³, Steven Collins³, Colin L Masters³, Alexander F Santillo¹⁹, Henrik Zetterberg^{20

21

22

23

24

25}, Kaj Blennow^{26

27

28

29}, Samuel F Berkovic³⁰, Dennis Velakoulis^{1

2}; MiND Study Group

Affiliations

¹ Neuropsychiatry Centre, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.
² Department of Psychiatry, The University of Melbourne, Melbourne, Victoria, Australia.
³ The Florey, Melbourne, Victoria, Australia.
⁴ Institute of Health and Wellbeing, Federation University, Melbourne, Victoria, Australia.
⁵ National Ageing Research Institute, Melbourne, Victoria, Australia.
⁶ Department of General Practice, The University of Melbourne, Melbourne, Victoria, Australia.
⁷ Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Melbourne, Victoria, Australia.
⁸ Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, Victoria, Australia.
⁹ School of Rural Health, Monash University, Melbourne, Victoria, Australia.
¹⁰ Melbourne School of Population & Global Health and Department of Medical Education, University of Melbourne, Melbourne, Victoria, Australia.
¹¹ Western Health, St. Albans, Victoria, Australia.
¹² Mildura Base Public Hospital, Melbourne, Victoria, Australia.
¹³ Alfred Mental and Addiction Health, Alfred Health, Melbourne, Victoria, Australia.
¹⁴ Ramsay Clinic Northside, Frederick St, Sydney, Australia.
¹⁵ Department of Psychiatry & Mental Health, Sarawak General Hospital, Kuching, Sarawak, Malaysia.
¹⁶ Neuroimmunology Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne, Victoria, Australia.
¹⁷ CORe, Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
¹⁸ Department of Psychiatry, The University of Melbourne, Austin Hospital, Melbourne, Victoria, Australia.
¹⁹ Department of Clinical Sciences, Clinical Memory Research Unit, Faculty of Medicine, Lund University, Malmö, Sweden.
²⁰ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
²¹ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
²² Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
²³ UK Dementia Research Institute at UCL, London, UK.
²⁴ Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
²⁵ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
²⁶ Institute of Neuroscience and Physiology, University of Gothenburg, Mölndal, Sweden.
²⁷ Clinical Neurochemistry Lab, Sahlgrenska University Hospital, Mölndal, Sweden.
²⁸ Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.
²⁹ Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, Anhui, P.R. China.
³⁰ Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Melbourne, Victoria, Australia.

PMID: 39369278
PMCID: PMC11567869
DOI: 10.1002/alz.14278

Plasma and CSF neurofilament light chain distinguish neurodegenerative from primary psychiatric conditions in a clinical setting

Dhamidhu Eratne et al. Alzheimers Dement. 2024 Nov.

. 2024 Nov;20(11):7989-8001.

doi: 10.1002/alz.14278. Epub 2024 Oct 6.

Authors

Affiliations

¹ Neuropsychiatry Centre, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.
² Department of Psychiatry, The University of Melbourne, Melbourne, Victoria, Australia.
³ The Florey, Melbourne, Victoria, Australia.
⁴ Institute of Health and Wellbeing, Federation University, Melbourne, Victoria, Australia.
⁵ National Ageing Research Institute, Melbourne, Victoria, Australia.
⁶ Department of General Practice, The University of Melbourne, Melbourne, Victoria, Australia.
⁷ Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Melbourne, Victoria, Australia.
⁸ Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, Victoria, Australia.
⁹ School of Rural Health, Monash University, Melbourne, Victoria, Australia.
¹⁰ Melbourne School of Population & Global Health and Department of Medical Education, University of Melbourne, Melbourne, Victoria, Australia.
¹¹ Western Health, St. Albans, Victoria, Australia.
¹² Mildura Base Public Hospital, Melbourne, Victoria, Australia.
¹³ Alfred Mental and Addiction Health, Alfred Health, Melbourne, Victoria, Australia.
¹⁴ Ramsay Clinic Northside, Frederick St, Sydney, Australia.
¹⁵ Department of Psychiatry & Mental Health, Sarawak General Hospital, Kuching, Sarawak, Malaysia.
¹⁶ Neuroimmunology Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne, Victoria, Australia.
¹⁷ CORe, Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
¹⁸ Department of Psychiatry, The University of Melbourne, Austin Hospital, Melbourne, Victoria, Australia.
¹⁹ Department of Clinical Sciences, Clinical Memory Research Unit, Faculty of Medicine, Lund University, Malmö, Sweden.
²⁰ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
²¹ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
²² Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
²³ UK Dementia Research Institute at UCL, London, UK.
²⁴ Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
²⁵ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
²⁶ Institute of Neuroscience and Physiology, University of Gothenburg, Mölndal, Sweden.
²⁷ Clinical Neurochemistry Lab, Sahlgrenska University Hospital, Mölndal, Sweden.
²⁸ Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.
²⁹ Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, Anhui, P.R. China.
³⁰ Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Melbourne, Victoria, Australia.

PMID: 39369278
PMCID: PMC11567869
DOI: 10.1002/alz.14278

Abstract

Introduction: People with neurodegenerative disorders (ND) frequently face diagnostic delay and misdiagnosis. We investigated blood and cerebrospinal fluid (CSF) neurofilament light chain (NfL) to distinguish ND from primary psychiatric disorders (PPD), a common challenge in clinical settings.

Methods: Plasma and CSF NfL levels were measured and compared between groups, adjusting for age, sex, and weight.

Results: A total of 337 participants were included: 136 ND, 77 PPD, and 124 Controls. Plasma NfL was 2.5-fold elevated in ND compared to PPD and had strong diagnostic performance (area under the curve, [AUC]: 0.86, 81%/85% specificity/sensitivity) that was comparable to CSF NfL (2-fold elevated, AUC: 0.89, 95%/71% specificity/sensitivity). Diagnostic performance was especially strong in younger people (40- < 60 years). Additional findings were cutoffs optimized for sensitivity and specificity, and issues important for future clinical translation.

Conclusions: This study adds important evidence for a simple blood-based biomarker to assist as a screening test for neurodegeneration and distinction from PPD, in clinical settings.

Highlights: NfL levels were significantly higher in ND versus PPD. Plasma NfL showed strong diagnostic performance, comparable to CSF NfL, to distinguish ND from PPD. Diagnostic performance was higher in younger people, where diagnostic challenges are greater. Further research is needed on analytical and reference range factors, for clinical translation. These findings support a simple screening blood test for neurodegeneration.

Keywords: biomarkers; dementia; diagnosis; neurofilament light chain protein; psychiatric disorders.

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Conflict of interest statement

H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche, 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). S.L. has received an honorarium from Lundbeck and previously received NHMRC funding. T.K. served on scientific advisory boards for MS International Federation and World Health Organisation, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck, and Biogen, the steering committee for Brain Atrophy Initiative by Sanofi Genzyme received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Roche, Sanofi‐Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck. K.B. has served as a consultant and on advisory boards for Abbvie, AC Immune, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, and Moleac Pte. Ltd, Neurimmune, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served on 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 Program, outside the work presented in this paper. K.B. is supported by the Swedish Research Council (#2017‐00915 and #2022‐00732), the Swedish Alzheimer Foundation (#AF‐930351, #AF‐939721, #AF‐968270, and #AF‐994551), Hjärnfonden, Sweden (#FO2017‐0243 and #ALZ2022‐0006), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF‐agreement (#ALFGBG‐715986 and #ALFGBG‐965240), the European Union Joint Program for Neurodegenerative Disorders (JPND2019‐466‐236), the Alzheimer's Association 2021 Zenith Award (ZEN‐21‐848495), the Alzheimer's Association 2022‐2025 Grant (SG‐23‐1038904 QC), La Fondation Recherche Alzheimer (FRA), Paris, France, the Kirsten and Freddy Johansen Foundation, Copenhagen, Denmark, and Familjen Rönströms Stiftelse, Stockholm, Sweden. This study was supported by funding from NHMRC (1185180), MACH MRFF RART 2.2, CJDSGN Memorial Award in memory of Michael Luscombe and RMH Foundation Spring Appeal. All the other authors have nothing to disclose. Author disclosures are available in the Supporting Information.

Figures

**FIGURE 1**
Plasma and CSF NfL levels in ND, PPD, and Controls. +, mean level. CSF, cerebrospinal fluid; NfL, neurofilament light chain; ND, neurodegenerative disorder; PPD, primary psychiatric disorder.

**FIGURE 2**
Receiver operator characteristic analysis curves for plasma and CSF NfL. CSF, cerebrospinal fluid; NfL, neurofilament light chain.

See this image and copyright information in PMC

References

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Plasma and CSF neurofilament light chain distinguish neurodegenerative from primary psychiatric conditions in a clinical setting

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Plasma and CSF neurofilament light chain distinguish neurodegenerative from primary psychiatric conditions in a clinical setting

Authors

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Abstract

Conflict of interest statement

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