Comparative Study

. 2024 Aug 16;95(9):822-828.

doi: 10.1136/jnnp-2023-332464.

NfL reliability across laboratories, stage-dependent diagnostic performance and matrix comparability in genetic FTD: a large GENFI study

Christoph Linnemann^{1

2}, Carlo Wilke^{3

4}, David Mengel^{3

4}, Henrik Zetterberg^{5

6}, Carolin Heller^{5

7}, Jens Kuhle⁸, Arabella Bouzigues⁷, Lucy L Russell⁷, Phoebe H Foster⁷, Eve Ferry-Bolder⁷, John Cornelis Van Swieten⁹, Lize C Jiskoot⁹, Harro Seelaar⁹, Fermin Moreno^{10

11}, Barbara Borroni¹², Raquel Sánchez-Valle¹³, Daniela Galimberti^{14

15}, Robert Laforce Jr¹⁶, Caroline Graff^{17

18}, Mario Masellis¹⁹, Maria Carmela Tartaglia²⁰, James Benedict Rowe²¹, Elizabeth Finger²², Rik Vandenberghe^{23

24}, Alexandre de Mendonca²⁵, Chris R Butler^{26

27}, Alexander Gerhard^{28

29}, Simon Ducharme^{30

31}, Isabelle L E Ber^{32

33}, Pietro Tiraboschi³⁴, Isabel Santana^{35

36}, Florence Pasquier^{37

38}, Johannes Levin^{39

40}, Markus Otto⁴¹, Sandro Sorbi^{42

43}, Jonathan Daniel Rohrer⁷, Matthis Synofzik^{1

4}; GENFI

Collaborators, Affiliations

Collaborators

GENFI:
Annabel Nelson, Martina Bocchetta, David Cash, David L Thomas, Emily Todd, Hanya Benotmane, Jennifer Nicholas, Kiran Samra, Rachelle Shafei, Carolyn Timberlake, Thomas Cope, Timothy Rittman, Antonella Alberici, Enrico Premi, Roberto Gasparotti, Valentina Cantoni, Emanuele Buratti, Andrea Arighi, Chiara Fenoglio, Elio Scarpini, Giorgio Fumagalli, Vittoria Borracci, Giacomina Rossi, Giorgio Giaccone, Giuseppe Di Fede, Paola Caroppo, Pietro Tiraboschi, Sara Prioni, Veronica Redaelli, David Tang-Wai, Ekaterina Rogaeva, Miguel Castelo-Branco, Morris Freedman, Ron Keren, Sandra Black, Sara Mitchell, Christen Shoesmith, Robart Bartha, Rosa Rademakers, Jackie Poos, Janne M Papma, Lucia Giannini, Rick van Minkelen, Yolande Pijnenburg, Benedetta Nacmias, Camilla Ferrari, Cristina Polito, Gemma Lombardi, Valentina Bessi, Michele Veldsman, Christin Andersson, Hakan Thonberg, Linn Öijerstedt, Vesna Jelic, Paul Thompson, Tobias Langheinrich, Albert Lladó, Anna Antonell, Jaume Olives, Mircea Balasa, Nuria Bargalló, Sergi Borrego-Ecija, Ana Verdelho, Carolina Maruta, Catarina B Ferreira, Gabriel Miltenberger, Tiago Coelho, Frederico Simões do Couto, Alazne Gabilondo, Ana Gorostidi, Jorge Villanua, Marta Cañada, Mikel Tainta, Miren Zulaica, Myriam Barandiaran, Patricia Alves, Benjamin Bender, Lisa Graf, Annick Vogels, Mathieu Vandenbulcke, Van Damme Philip, Rose Bruffaerts, Koen Poesen, Pedro Rosa-Neto, Serge Gauthier, Agnès Camuzat, Alexis Brice, Anne Bertrand, Aurélie Funkiewiez, Daisy Rinaldi, Dario Saracino, Olivier Colliot, Sabrina Sayah, Catharina Prix, Elisabeth Wlasich, Olivia Wagemann, Sandra Loosli, Sonja Schönecker, Tobias Hoegen, Jolina Lombardi, Sarah Anderl-Straub, Adeline Rollin, Gregory Kuchcinski, Maxime Bertoux, Thibaud Lebouvier, Vincent Deramecourt, Beatriz Santiago, Diana Duro, Maria João Leitão, Maria Rosario Almeida, Miguel Tábuas-Pereira, Sónia Afonso

Affiliations

¹ Division Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany matthis.synofzik@uni-tuebingen.de christoph.linnemann@upk.ch.
² Center of Old Age Psychiatry, Psychiatric University Hospital (UPK), University of Basel, Basel, Switzerland.
³ Division Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany.
⁴ Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
⁵ UK Dementia Research Institute at UCL, London, UK.
⁶ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
⁷ Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
⁸ Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel, University of Basel, Basel, Switzerland.
⁹ Department of Neurology, Erasmus Medical Centre, Rotterdam, Netherlands.
¹⁰ Cognitive Disorders Unit, Department of Neurology, Donostia Universitary Hospital, San Sebastian, Spain.
¹¹ Biodonostia Health Research Institute, Neuroscience Area, San Sebastian, Spain.
¹² Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
¹³ Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Institut d'Investigacións Biomèdiques August Pi I Sunyer, University of Barcelona, Barcelona, Spain.
¹⁴ IRCCS Ospedale Policlinico, Fondazione Ca' Granda, Milan, Italy.
¹⁵ Centro Dino Ferrari, University of Milan, Milan, Italy.
¹⁶ Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, CHU de Québec, and Faculté de Médecine, Université Laval, Québec, Alberta, Canada.
¹⁷ Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institutet, Solna, Sweden.
¹⁸ Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital, Solna, Sweden.
¹⁹ Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.
²⁰ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
²¹ Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
²² Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada.
²³ Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium.
²⁴ Neurology Service, University Hospitals Leuven, Leuven, Belgium.
²⁵ Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
²⁶ Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, UK.
²⁷ Department of Brain Sciences, Imperial College, London, UK.
²⁸ Division of Neuroscience and Experimental Psychology, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK.
²⁹ Department of Geriatric Medicine, Klinikum Hochsauerland, Arnsberg, Germany.
³⁰ Department of Psychiatry, McGill University Health Centre, McGill University, Montreal, Québec, Canada.
³¹ McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada.
³² Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
³³ Centre de référence des démences rares ou précoces, IM2A, Département de Neurologie, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
³⁴ Istituto Neurologico Carlo Besta, Fondazione IRCCS, Milan, Italy.
³⁵ Neurology Service, Faculty of Medicine, University Hospital of Coimbra (HUC), University of Coimbra, Coimbra, Portugal.
³⁶ Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
³⁷ University of Lille, Lille, France.
³⁸ Inserm 1172, Lille, France.
³⁹ Department of Neurology, Ludwig-Maximilians Universität München, Munich, Germany.
⁴⁰ German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
⁴¹ Department of Neurology, University of Ulm, Ulm, Germany.
⁴² Department of Neurofarba, University of Florence, Firenze, Italy.
⁴³ Don Carlo Gnocchi, IRCCS Fondazione, Firenze, Italy.

PMID: 38253362
PMCID: PMC11347244
DOI: 10.1136/jnnp-2023-332464

Comparative Study

NfL reliability across laboratories, stage-dependent diagnostic performance and matrix comparability in genetic FTD: a large GENFI study

Christoph Linnemann et al. J Neurol Neurosurg Psychiatry. 2024.

. 2024 Aug 16;95(9):822-828.

doi: 10.1136/jnnp-2023-332464.

Authors

Collaborators

GENFI:
Annabel Nelson, Martina Bocchetta, David Cash, David L Thomas, Emily Todd, Hanya Benotmane, Jennifer Nicholas, Kiran Samra, Rachelle Shafei, Carolyn Timberlake, Thomas Cope, Timothy Rittman, Antonella Alberici, Enrico Premi, Roberto Gasparotti, Valentina Cantoni, Emanuele Buratti, Andrea Arighi, Chiara Fenoglio, Elio Scarpini, Giorgio Fumagalli, Vittoria Borracci, Giacomina Rossi, Giorgio Giaccone, Giuseppe Di Fede, Paola Caroppo, Pietro Tiraboschi, Sara Prioni, Veronica Redaelli, David Tang-Wai, Ekaterina Rogaeva, Miguel Castelo-Branco, Morris Freedman, Ron Keren, Sandra Black, Sara Mitchell, Christen Shoesmith, Robart Bartha, Rosa Rademakers, Jackie Poos, Janne M Papma, Lucia Giannini, Rick van Minkelen, Yolande Pijnenburg, Benedetta Nacmias, Camilla Ferrari, Cristina Polito, Gemma Lombardi, Valentina Bessi, Michele Veldsman, Christin Andersson, Hakan Thonberg, Linn Öijerstedt, Vesna Jelic, Paul Thompson, Tobias Langheinrich, Albert Lladó, Anna Antonell, Jaume Olives, Mircea Balasa, Nuria Bargalló, Sergi Borrego-Ecija, Ana Verdelho, Carolina Maruta, Catarina B Ferreira, Gabriel Miltenberger, Tiago Coelho, Frederico Simões do Couto, Alazne Gabilondo, Ana Gorostidi, Jorge Villanua, Marta Cañada, Mikel Tainta, Miren Zulaica, Myriam Barandiaran, Patricia Alves, Benjamin Bender, Lisa Graf, Annick Vogels, Mathieu Vandenbulcke, Van Damme Philip, Rose Bruffaerts, Koen Poesen, Pedro Rosa-Neto, Serge Gauthier, Agnès Camuzat, Alexis Brice, Anne Bertrand, Aurélie Funkiewiez, Daisy Rinaldi, Dario Saracino, Olivier Colliot, Sabrina Sayah, Catharina Prix, Elisabeth Wlasich, Olivia Wagemann, Sandra Loosli, Sonja Schönecker, Tobias Hoegen, Jolina Lombardi, Sarah Anderl-Straub, Adeline Rollin, Gregory Kuchcinski, Maxime Bertoux, Thibaud Lebouvier, Vincent Deramecourt, Beatriz Santiago, Diana Duro, Maria João Leitão, Maria Rosario Almeida, Miguel Tábuas-Pereira, Sónia Afonso

Affiliations

¹ Division Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany matthis.synofzik@uni-tuebingen.de christoph.linnemann@upk.ch.
² Center of Old Age Psychiatry, Psychiatric University Hospital (UPK), University of Basel, Basel, Switzerland.
³ Division Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany.
⁴ Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
⁵ UK Dementia Research Institute at UCL, London, UK.
⁶ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
⁷ Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
⁸ Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel, University of Basel, Basel, Switzerland.
⁹ Department of Neurology, Erasmus Medical Centre, Rotterdam, Netherlands.
¹⁰ Cognitive Disorders Unit, Department of Neurology, Donostia Universitary Hospital, San Sebastian, Spain.
¹¹ Biodonostia Health Research Institute, Neuroscience Area, San Sebastian, Spain.
¹² Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
¹³ Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Institut d'Investigacións Biomèdiques August Pi I Sunyer, University of Barcelona, Barcelona, Spain.
¹⁴ IRCCS Ospedale Policlinico, Fondazione Ca' Granda, Milan, Italy.
¹⁵ Centro Dino Ferrari, University of Milan, Milan, Italy.
¹⁶ Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, CHU de Québec, and Faculté de Médecine, Université Laval, Québec, Alberta, Canada.
¹⁷ Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institutet, Solna, Sweden.
¹⁸ Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital, Solna, Sweden.
¹⁹ Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.
²⁰ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
²¹ Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
²² Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada.
²³ Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium.
²⁴ Neurology Service, University Hospitals Leuven, Leuven, Belgium.
²⁵ Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
²⁶ Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, UK.
²⁷ Department of Brain Sciences, Imperial College, London, UK.
²⁸ Division of Neuroscience and Experimental Psychology, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK.
²⁹ Department of Geriatric Medicine, Klinikum Hochsauerland, Arnsberg, Germany.
³⁰ Department of Psychiatry, McGill University Health Centre, McGill University, Montreal, Québec, Canada.
³¹ McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada.
³² Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
³³ Centre de référence des démences rares ou précoces, IM2A, Département de Neurologie, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
³⁴ Istituto Neurologico Carlo Besta, Fondazione IRCCS, Milan, Italy.
³⁵ Neurology Service, Faculty of Medicine, University Hospital of Coimbra (HUC), University of Coimbra, Coimbra, Portugal.
³⁶ Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
³⁷ University of Lille, Lille, France.
³⁸ Inserm 1172, Lille, France.
³⁹ Department of Neurology, Ludwig-Maximilians Universität München, Munich, Germany.
⁴⁰ German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
⁴¹ Department of Neurology, University of Ulm, Ulm, Germany.
⁴² Department of Neurofarba, University of Florence, Firenze, Italy.
⁴³ Don Carlo Gnocchi, IRCCS Fondazione, Firenze, Italy.

PMID: 38253362
PMCID: PMC11347244
DOI: 10.1136/jnnp-2023-332464

Abstract

Background: Blood neurofilament light chain (NfL) is increasingly considered as a key trial biomarker in genetic frontotemporal dementia (gFTD). We aimed to facilitate the use of NfL in gFTD multicentre trials by testing its (1) reliability across labs; (2) reliability to stratify gFTD disease stages; (3) comparability between blood matrices and (4) stability across recruiting sites.

Methods: Comparative analysis of blood NfL levels in a large gFTD cohort (GENFI) for (1)-(4), with n=344 samples (n=148 presymptomatic, n=11 converter, n=46 symptomatic subjects, with mutations in C9orf72, GRN or MAPT; and n=139 within-family controls), each measured in three different international labs by Simoa HD-1 analyzer.

Results: NfL revealed an excellent consistency (intraclass correlation coefficient (ICC) 0.964) and high reliability across the three labs (maximal bias (pg/mL) in Bland-Altman analysis: 1.12±1.20). High concordance of NfL across laboratories was moreover reflected by high areas under the curve for discriminating conversion stage against the (non-converting) presymptomatic stage across all three labs. Serum and plasma NfL were largely comparable (ICC 0.967). The robustness of NfL across 13 recruiting sites was demonstrated by a linear mixed effect model.

Conclusions: Our results underline the suitability of blood NfL in gFTD multicentre trials, including cross-lab reliable stratification of the highly trial-relevant conversion stage, matrix comparability and cross-site robustness.

Keywords: COGNITION; FRONTOTEMPORAL DEMENTIA; NEUROPSYCHIATRY.

PubMed Disclaimer

Conflict of interest statement

Competing interests: HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, 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 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). JK received speaker fees, research support, travel support, and/or served on advisory boards by Swiss MS Society, Swiss National Research Foundation (320030_189140/1), University of Basel, Progressive MS Alliance, Alnylam, Bayer, Biogen, Bristol Myers Squibb, Celgene, Immunic, Merck, Neurogenesis, Novartis, Octave Bioscience, Quanterix, Roche, Sanofi, Stata DX. MS has received consultancy honoraria from Ionis, UCB, Prevail, Orphazyme, Servier, Reata, GenOrph, AviadoBio, Biohaven, Zevra,and Lilly, all unrelated to the present manuscript. The other authors declare no competing interests.

Figures

**Figure 1**
Cross-lab reliability, cross-lab disease-stage cut-offs and likelihood ratios (LR) and blood matrix comparability in genetic FTD. (A) Reliability of blood NfL measurements in genetic FTD (gFTD) across three labs (lab 1 and 2 serum, lab 3 plasma)—linear regressions and Bland-Altman analyses of log-transformed NfL values. For detailed statistics, see online supplemental table 2. (B) Comparative across-lab analysis of ROC curves and AUC values for the condition ‘presymptomatic versus symptomatic carriers’. Detailed values of AUC±SE and 95% CI are given in the Results section. (C) Reliability of AUC values across three labs—Bland-Altman analyses for all stage comparisons. For detailed statistics, see online supplemental table 2. (D) Prediction of individual risk factors at different cut-offs for the condition ‘presymptomatic versus symptomatic carriers’ (age-corrected z-values, first lab) by positive (LR+) and negative (LR−). AUC, area under the curve; FTD, frontotemporal dementia; NfL, neurofilament light chain; ROC receiver operating characteristic

See this image and copyright information in PMC

References

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NfL reliability across laboratories, stage-dependent diagnostic performance and matrix comparability in genetic FTD: a large GENFI study

Collaborators

Affiliations

NfL reliability across laboratories, stage-dependent diagnostic performance and matrix comparability in genetic FTD: a large GENFI study

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

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Grants and funding

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