Objective: People with neuropsychiatric symptoms often experience delay in accurate diagnosis. Although cerebrospinal fluid neurofilament light (CSF NfL) shows promise in distinguishing neurodegenerative disorders (ND) from psychiatric disorders (PSY), its accuracy in a diagnostically challenging cohort longitudinally is unknown. Methods: We collected longitudinal diagnostic information (mean=36 months) from patients assessed at a neuropsychiatry service, categorising diagnoses as ND/mild cognitive impairment/other neurological disorders (ND/MCI/other), and PSY. We pre-specified NfL>582pg/mL as indicative of ND/MCI/other. Results: Diagnostic category changed from initial to final diagnosis for 23% (49/212) of patients. NfL predicted the final diagnostic category for 92% (22/24) of these and predicted final diagnostic category overall (ND/MCI/other vs. PSY) in 88% (187/212), compared to 77% (163/212) with clinical assessment alone. Conclusions: CSF NfL improved diagnostic accuracy, with potential to have led to earlier, accurate diagnosis in a real-world setting using a pre-specified cut-off, adding weight to translation of NfL into clinical practice.

Steven Collins has acted as a paid consultant to Biogen Australia. Henrik Zetterberg: HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Passage Bio, Pinteon Therapeutics, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, 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). Charles Malpas has received conference travel support from Merck, Novartis, and Biogen. He has received research support from the National Health and Medical Research Council, Multiple Sclerosis Research Australia, The University of Melbourne, The Royal Melbourne Hospital Neuroscience Foundation, and Dementia Australia. Kaj Blennow has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Ono Pharma, Pharmatrophix, Prothena, Roche Diagnostics, and Siemens Healthineers, 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. Mark Walterfang has served as a consultant, at advisory boards, or on data monitoring committees for Actelion, Vtesse, Sucampo, Mallinckrodt, and Biomarin Pharmaceuticals; has received investigator grants from Pfizer, Lilly, Bristol Meyers Squibb, Actelion, Vtesse, and Mallinckrodt pharmaceuticals; the National Health and Medical Research Council, the Royal Melbourne Hospital, the Ara Parseghian Medical Research Foundation, the Bethlehem Griffiths Foundation, and the CHDI Initiative. He has received travel support from Lilly, Pfizer, Actelion, Orphan, Biomarin, Vtesse and Sucampo Pharmaceuticals. Tomas Kalincik served on scientific advisory boards for MS International Federation and World Health Organisation, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck and Biogen, 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. Sarah Farrand has received honoraria from Abbvie, Abbott and a fellowship from Medtronic.

We are grateful for funding that supported this work: the Trisno Family Research Grant in Old Age Psychiatry, three NorthWestern Mental Health Research Seed Grants, MACH MRFF, and NHMRC (1185180). Alexander F Santilli has been supported specifically for this project by The Fromma Foundation, The Ellen and Henrik Sjobring Foundation, and the Fredrik and Ingrid Thuring Foundation. Henrik Zetterberg is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018 02532), the European Research Council (#681712 and #101053962), Swedish State Support for Clinical Research (#ALFGBG 71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809 2016862), the AD Strategic Fund and the Alzheimers Association (#ADSF 21 831376 C, #ADSF 21 831381 C and #ADSF 21 831377 C), the Bluefield Project, the Olav Thon Foundation, the Erling Persson Family Foundation, Stiftelsen for Gamla Tjanarinnor, Hjarnfonden, Sweden (#FO2022 0270), the European Unions Horizon 2020 research and innovation programme under the Marie Sklodowska Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme Neurodegenerative Disease Research (JPND2021 00694), and the UK Dementia Research Institute at UCL (UKDRI 1003). Kaj Blennow is supported by the Swedish Research Council (#2017 00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB 201809 2016615), the Swedish Alzheimer Foundation (#AF 930351, #AF 939721 and #AF 968270), Hjarnfonden, 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 National Institute of Health (NIH), USA, (grant #1R01AG068398 01), and the Alzheimers Association 2021 Zenith Award (ZEN 21 848495). AHE reports honoraria for presentations from Merck, Allergan, Ipsen, Teva, UCB, Abbott, AbbVie, Pfizer, STADA. Participation in scientific advisory board meetings with Allergan, AbbVie, Ipsen, Pfizer and STADA. He holds shares in GKC and CSL.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Human Research Ethics Committees at Melbourne Health gave ethical approval for this work (2016.038, 2017.090, 2018.371, 2020.142) Ethics Committee at University of Melbourne gave ethical approval for this work (1341074, 1648441.3).

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All data produced in the present study are available upon reasonable request to the authors