. 2022 Apr 19;3(4):100607.

doi: 10.1016/j.xcrm.2022.100607.

Comprehensive cross-sectional and longitudinal analyses of plasma neurofilament light across FTD spectrum disorders

Tania F Gendron¹, Michael G Heckman², Launia J White², Austin M Veire³, Otto Pedraza⁴, Alexander R Burch⁵, Andrea C Bozoki⁶, Bradford C Dickerson⁷, Kimiko Domoto-Reilly⁸, Tatiana Foroud⁹, Leah K Forsberg¹⁰, Douglas R Galasko¹¹, Nupur Ghoshal¹², Neill R Graff-Radford⁵, Murray Grossman¹³, Hilary W Heuer¹⁴, Edward D Huey¹⁵, Ging-Yuek R Hsiung¹⁶, David J Irwin¹⁷, Daniel I Kaufer⁶, Gabriel C Leger¹¹, Irene Litvan¹¹, Joseph C Masdeu¹⁸, Mario F Mendez¹⁹, Chiadi U Onyike²⁰, Belen Pascual¹⁸, Aaron Ritter²¹, Erik D Roberson²², Julio C Rojas¹⁴, Maria Carmela Tartaglia²³, Zbigniew K Wszolek⁵, Howard Rosen¹⁴, Bradley F Boeve¹⁰, Adam L Boxer¹⁴; ALLFTD consortium; Leonard Petrucelli²⁴

Collaborators, Affiliations

Collaborators

ALLFTD consortium:
Brian S Appleby, Sami Barmada, Yvette Bordelon, Hugo Botha, Danielle Brushaber, David Clark, Giovanni Coppola, Ryan Darby, Katrina Devick, Dennis Dickson, Kelley Faber, Anne Fagan, Julie A Fields, Ralitza Gavrilova, Daniel Geschwind, Jill Goldman, Jonathon Graff-Radford, Ian Grant, David T Jones, Kejal Kantarci, Diana Kerwin, David S Knopman, John Kornak, Walter Kremers, Maria Lapid, Argentina Lario Lago, Peter Ljubenkov, Diane Lucente, Ian R Mackenzie, Scott McGinnis, Carly Mester, Bruce L Miller, Peter Pressman, Rosa Rademakers, Vijay K Ramanan, E Marisa Ramos, Katherine P Rankin, Meghana Rao, Katya Rascovsky, Rodolfo Savica, William Seeley, Adam M Staffaroni, Jeremy Syrjanen, Jack Taylor, Lawren VandeVrede, Sandra Weintraub, Bonnie Wong

Affiliations

¹ Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: Gendron.Tania@mayo.edu.
² Division of Clinical Trials and Biostatistics, Mayo Clinic, Jacksonville, FL 32224, USA.
³ Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
⁴ Department of Psychiatry & Psychology, Mayo Clinic, Jacksonville, FL 32224, USA.
⁵ Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA.
⁶ Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁷ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
⁸ Department of Neurology, University of Washington, Seattle, WA 98104, USA.
⁹ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
¹⁰ Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
¹¹ Parkinson and Other Movement Disorder Center, Department of Neuroscience, University of California, San Diego, La Jolla, CA 92037, USA.
¹² Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
¹³ Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁴ Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
¹⁵ Department of Psychiatry, Taub Institute, Columbia University, New York, NY 10032, USA; Department of Neurology, Taub Institute, Columbia University, New York, NY 10032, USA.
¹⁶ Centre for Brain Health, Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
¹⁷ Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
¹⁸ Nantz National Alzheimer Center, Stanley H. Appel Department of Neurology, Houston Methodist Research Institute, Weill Cornell Medicine, Houston, TX 77030, USA.
¹⁹ Department of Neurology, University of California at Los Angeles, Los Angeles, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, Los Angeles, CA 90095, USA.
²⁰ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD 21287, USA.
²¹ Neurological Institute, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV 89106, USA.
²² Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
²³ Krembil Brain Institute, Tanz Centre for Research in Neurodegenerative Diseases, Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
²⁴ Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: Petrucelli.Leonard@mayo.edu.

PMID: 35492244
PMCID: PMC9044101
DOI: 10.1016/j.xcrm.2022.100607

Comprehensive cross-sectional and longitudinal analyses of plasma neurofilament light across FTD spectrum disorders

Tania F Gendron et al. Cell Rep Med. 2022.

. 2022 Apr 19;3(4):100607.

doi: 10.1016/j.xcrm.2022.100607.

Authors

Collaborators

ALLFTD consortium:
Brian S Appleby, Sami Barmada, Yvette Bordelon, Hugo Botha, Danielle Brushaber, David Clark, Giovanni Coppola, Ryan Darby, Katrina Devick, Dennis Dickson, Kelley Faber, Anne Fagan, Julie A Fields, Ralitza Gavrilova, Daniel Geschwind, Jill Goldman, Jonathon Graff-Radford, Ian Grant, David T Jones, Kejal Kantarci, Diana Kerwin, David S Knopman, John Kornak, Walter Kremers, Maria Lapid, Argentina Lario Lago, Peter Ljubenkov, Diane Lucente, Ian R Mackenzie, Scott McGinnis, Carly Mester, Bruce L Miller, Peter Pressman, Rosa Rademakers, Vijay K Ramanan, E Marisa Ramos, Katherine P Rankin, Meghana Rao, Katya Rascovsky, Rodolfo Savica, William Seeley, Adam M Staffaroni, Jeremy Syrjanen, Jack Taylor, Lawren VandeVrede, Sandra Weintraub, Bonnie Wong

Affiliations

¹ Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: Gendron.Tania@mayo.edu.
² Division of Clinical Trials and Biostatistics, Mayo Clinic, Jacksonville, FL 32224, USA.
³ Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
⁴ Department of Psychiatry & Psychology, Mayo Clinic, Jacksonville, FL 32224, USA.
⁵ Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA.
⁶ Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁷ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
⁸ Department of Neurology, University of Washington, Seattle, WA 98104, USA.
⁹ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
¹⁰ Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
¹¹ Parkinson and Other Movement Disorder Center, Department of Neuroscience, University of California, San Diego, La Jolla, CA 92037, USA.
¹² Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
¹³ Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁴ Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
¹⁵ Department of Psychiatry, Taub Institute, Columbia University, New York, NY 10032, USA; Department of Neurology, Taub Institute, Columbia University, New York, NY 10032, USA.
¹⁶ Centre for Brain Health, Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
¹⁷ Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
¹⁸ Nantz National Alzheimer Center, Stanley H. Appel Department of Neurology, Houston Methodist Research Institute, Weill Cornell Medicine, Houston, TX 77030, USA.
¹⁹ Department of Neurology, University of California at Los Angeles, Los Angeles, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, Los Angeles, CA 90095, USA.
²⁰ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD 21287, USA.
²¹ Neurological Institute, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV 89106, USA.
²² Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
²³ Krembil Brain Institute, Tanz Centre for Research in Neurodegenerative Diseases, Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
²⁴ Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: Petrucelli.Leonard@mayo.edu.

PMID: 35492244
PMCID: PMC9044101
DOI: 10.1016/j.xcrm.2022.100607

Abstract

Frontotemporal dementia (FTD) therapy development is hamstrung by a lack of susceptibility, diagnostic, and prognostic biomarkers. Blood neurofilament light (NfL) shows promise as a biomarker, but studies have largely focused only on core FTD syndromes, often grouping patients with different diagnoses. To expedite the clinical translation of NfL, we avail ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study resources and conduct a comprehensive investigation of plasma NfL across FTD syndromes and in presymptomatic FTD mutation carriers. We find plasma NfL is elevated in all studied syndromes, including mild cases; increases in presymptomatic mutation carriers prior to phenoconversion; and associates with indicators of disease severity. By facilitating the identification of individuals at risk of phenoconversion, and the early diagnosis of FTD, plasma NfL can aid in participant selection for prevention or early treatment trials. Moreover, its prognostic utility would improve patient care, clinical trial efficiency, and treatment outcome estimations.

Trial registration: ClinicalTrials.gov NCT02372773 NCT02365922.

Keywords: Richardson’s syndrome; behavioral variant frontotemporal dementia; biomarker; corticobasal syndrome; neurofilament light; plasma; presymptomatic; primary progressive aphasia; progressive supranuclear palsy.

PubMed Disclaimer

Conflict of interest statement

A.C.B. is site PI for the Alector INFRONT-3 trial. A.L.B. receives research support from NIH (R01AG038791, R01AG073482, and U24AG057437), Rainwater Charitable Foundation, Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, Alzheimer’s Drug Discovery Foundation, and the Alzheimer’s Association. He has served as a consultant for Alector, AGTC, Arkuda, Arvinas, AZTherapies, GSK, Oligomerix, Ono, Roche, Samumed, Stealth, Third Rock, Transposon, TrueBinding, and Wave and received research support from Biogen, Eisai, and Regeneron. B.F.B. has served as an investigator for clinical trials sponsored by Biogen, Alector, and EIP Pharma. He receives royalties from a published book entitled Behavioral Neurology of Dementia (Cambridge Medicine, 2009, 2017), serves on the Tau Consortium Scientific Advisory Board, and receives research support from the NIH. B.C.D. consults for Acadia, Arkuda, Axovant, Lilly, Biogen, Merck, Novartis, and Wave LifeSciences; has Elsevier editorial duties with payment (Neuroimage: Clinical and Cortex); and receives royalties from Oxford University Press and Cambridge University Press. K.D.-R. has research funding from Biogen and Lawson Health Research Institute and receives consultant fees from Biogen and educational fees from MedBridge. D.R.G. consults for Biogen, Fujirebio, and Amprion and is on the DSMB for Cognition Therapeutics. M.G. is participating in treatment trials sponsored by Alector, Prevail, and Passage Bio and is a consultant to Takeda, Passage Bio, and Biogen. N.G. has or is participating in clinical trials of anti-dementia drugs sponsored by Bristol Myers Squibb, Lilly/Avid Radiopharmaceuticals, Janssen, Novartis, Pfizer, and Wyeth. N.R.G.-R. has taken part in multicenter studies funded by Biogen, AbbVie, and Lilly. G.-Y.R.H. has received research support from Anavax, Biogen, and Roche. I.L. received support from Roche, Abbvie, Biogen, EIP-Pharma, and Biohaven Pharmaceuticals; was member of a Lundbeck Advisory Board; and receives salary from the University of California, San Diego and as Chief Editor of Frontiers in Neurology. J.C.M. participates on a speaker forum for Biogen and receives research support from Biogen, Eisai, Eli Lilly, Green Valley, and Novartis. C.U.O. is a consultant with Alector and Acadia and receives research funding from Alector. L.P. is a consultant for Expansion Therapeutics. E.D.R. receives funding from NIH, Alzheimer’s Drug Discovery Foundation, Bluefield Project, and Alector; consults for Biogen, AVROBIO, and AGTC; and owns intellectual property related to tau. J.C.R. is a site PI for Eli Lilly and Eisai clinical trials and receives research support from NIH K23AG059888. M.C.T. participates in clinical trials with Biogen, Avanex, UCB, and Janssen. Z.K.W. is supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, Mayo Clinic in Florida Focused Research Team Program, the gifts from The Sol Goldman Charitable Trust, the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and The Albertson Parkinson’s Research Foundation. He serves as PI or co-PI on Biohaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301); Neuraly, Inc. (NLY01-PD-1); and Vigil Neuroscience, Inc. (VGL101–01.001) grants. He serves as co-PI of the Mayo Clinic APDA Center for Advanced Research and as an external advisory board member for Vigil Neuroscience, Inc. All other authors report no competing interests.

Figures

**Figure 1**
Plasma NfL concentrations associate with age, gender, and symptom duration in some phenotype groups Associations of baseline NfL concentrations with age (A), gender (B), and symptom duration (C) assessed using linear regression models adjusted for age, gender, and symptom duration. β coefficients (β), 95% confidence intervals (CIs), and p values are shown for significant associations, where p < 0.025 is considered significant for controls and presymptomatic mutation carriers and p <0.0167 is considered significant for symptomatic groups. In (B), black horizontal bars represent median NfL concentrations. Gray circles represent 11 bvFTD patients and five CBS patients with unknown mutation status, one bvFTD patient with a likely pathogenic *GRN* variant and three with a *TARDBP* mutation, and one CBS patient with an intermediate *C9orf72* repeat expansion. NfL in plasma samples was measured in duplicate, and the mean concentration of replicates is shown on the base 10 logarithm scale. See Figures S1A–S1C to view NfL concentrations on the linear scale and also see Table S2. The number of individuals per group (n) is shown in figure panels and in Tables 1 and S1.

**Figure 2**
Baseline plasma NfL is elevated in presymptomatic mutation carriers and all symptomatic groups (A) Comparison of baseline plasma NfL between healthy controls or presymptomatic mutation carriers and symptomatic groups. (B) Comparison of baseline NfL between presymptomatic carriers who phenoconverted and controls or presymptomatic carriers who remained asymptomatic for at least 1 year. (C) Comparison of baseline NfL between controls or presymptomatic carriers and patients in symptomatic groups with a CDR + NACC-FTLD global score of 0 or 0.5. (D) Heatmap showing AUCs comparing controls to the indicated groups that include all individuals of a given group (all subjects) or only those with an CDR + NACC-FTLD global score of 0 or 0.5 (mildly impaired) from unadjusted or age- and gender-adjusted analyses. (E) Comparison of baseline plasma NfL between non-mutation carriers and mutation carriers for clinically normal individuals and patients with bvFTD or MCI. Data in (E) do not include the two presymptomatic carriers with a mutation in both *C9orf72* and *GRN*. p values are from analysis adjusted for age and gender. ∗∗∗p < 0.001 and ∗∗p < 0.01, comparison to controls; ^###p < 0.001 and ^##p = 0.003, comparison to presymptomatic carriers; ^ǂǂǂp < 0.001, comparison with presymptomatic non-converters. Horizontal bars represent median NfL concentrations. NfL in plasma samples was measured in duplicate, and the mean concentration of replicates is shown on the base 10 logarithm scale. See Figures S1D and S1E to view NfL concentrations on the linear scale. Relating to (A)–(D), see also Tables S3–S7. Relating to (E), see also Tables S8 and S9. The number of individuals per group (n) is shown in figure panels and in Tables 1 and S1.

**Figure 3**
Plasma NfL increases throughout presymptomatic and symptomatic disease phases (A) Longitudinal NfL concentrations are depicted for the indicated phenotype groups. NfL in plasma samples was measured in duplicate, and the mean concentration of replicates is shown on the base 10 logarithm scale. (B) For individuals with one or more serial NfL measurements at least 1 year from baseline, we show comparisons of rate of change in NfL concentration per year for controls, all presymptomatic mutation carriers (all PreSx), presymptomatic carriers who did not convert (non-conv), those that did phenoconvert (phenoconv), and patients with MCI, bvFTD, PPA, or parkinsonian disorders. p values from analysis comparing rates of NfL change between the indicated group and either controls, non-converters, or phenoconverters after adjusting for age and gender are shown. The number of individuals per group (n) is shown in figure panels and in Tables 1 and S1. See also Tables S13 and S14.

**Figure 4**
Longitudinal profiles and rates of NfL change in presymptomatic individuals and patients with bvFTD according to mutation status (A) Longitudinal NfL concentrations are depicted for clinically normal individuals and bvFTD patients with no mutation or a mutation in *C9orf72*, *GRN*, or *MAPT*. NfL in plasma samples was measured in duplicate, and the mean concentration of replicates is shown on the base 10 logarithm scale. (B) For individuals with one or more serial NfL measurements at least 1 year from baseline, we show comparisons of rate of change in NfL concentration per year between controls and presymptomatic mutation carriers or bvFTD patients according to mutation status. Patients with bvFTD without a mutation (n = 4) or with a *GRN* mutation (n = 4) were not included in the analysis. p values from analysis comparing rates of NfL change between the indicated group and controls after adjusting for age and gender are presented. Longitudinal data for the presymptomatic carrier with a mutation in both *C9orf72* and *GRN* are not included in (A) or (B). The number of individuals per group (n) is shown in figure panels and in Tables 1 and S1. See also Tables S13 and S15.

**Figure 5**
Temporal trajectories of plasma NfL in presymptomatic individuals and individuals with MCI who phenoconverted according to mutation status Shown, according to mutation status, are longitudinal NfL concentrations for 23 mutation carriers who phenoconverted (i.e., 14 from presymptomatic to symptomatic and nine from MCI to bvFTD). For five individuals, plasma NfL was not available from the follow-up visit at which their diagnosis changed; these individuals are marked by a white circle partially shaded in black for clinically normal individuals later diagnosed with MCI or by a gray square partially shaded in black for a patient with MCI subsequently diagnosed with bvFTD. NfL in plasma samples was measured in duplicate, and mean concentrations are shown on the base 10 logarithm scale. CN, clinically normal; PD, Parkinson’s disease.

See this image and copyright information in PMC

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Comprehensive cross-sectional and longitudinal analyses of plasma neurofilament light across FTD spectrum disorders

Collaborators

Affiliations

Comprehensive cross-sectional and longitudinal analyses of plasma neurofilament light across FTD spectrum disorders

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Medical