Comparative Study

. 2025 Mar 12;20(1):30.

doi: 10.1186/s13024-025-00821-4.

Comprehensive cross-sectional and longitudinal comparisons of plasma glial fibrillary acidic protein and neurofilament light across FTD spectrum disorders

Udit Sheth^{1

2}, Linn Öijerstedt¹, Michael G Heckman³, Launia J White³, Hilary W Heuer⁴, Argentina Lario Lago⁴, Leah K Forsberg⁵, Kelley M Faber⁶, Tatiana M Foroud⁶, Rosa Rademakers^{1

7

8}, Eliana Marisa Ramos⁹, Brian S Appleby¹⁰, Andrea C Bozoki¹¹, R Ryan Darby¹², Bradford C Dickerson¹³, Kimiko Domoto-Reilly¹⁴, Douglas R Galasko¹⁵, Nupur Ghoshal¹⁶, Neill R Graff-Radford¹⁷, Ian M Grant¹⁸, Chadwick M Hales¹⁹, Ging-Yuek Robin Hsiung²⁰, Edward D Huey²¹, David Irwin²², Justin Y Kwan²³, Irene Litvan²⁴, Ian R Mackenzie²⁵, Joseph C Masdeu²⁶, Mario F Mendez⁹, Chiadi U Onyike²⁷, Belen Pascual²⁶, Peter S Pressman^{28

29}, Erik D Roberson³⁰, Allison Snyder²³, M Carmela Tartaglia³¹, William W Seeley^{4

32}, Dennis W Dickson¹, Howard J Rosen⁴, Bradley F Boeve⁵, Adam L Boxer⁴, Leonard Petrucelli^{1

2}, Tania F Gendron^{33

34}

Affiliations

¹ Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
² Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
³ Division of Clinical Trials and Biostatistics, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
⁴ Memory and Aging Center, Department of Neurology, University of California San Francisco, 675 Nelson Rising Lane, San Francisco, CA, 91358, USA.
⁵ Department of Neurology, Mayo Clinic, 200 First St, SW, Rochester, MN, 55905, USA.
⁶ Department of Medical and Molecular Genetics, The National Centralized Repository for Alzheimer's Disease and Related Dementias, 351 W. 10Th St TK-217, Indianapolis, IN, 46202, USA.
⁷ Department of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.
⁸ VIB Center for Molecular Neurology, VIB, Universiteitsplein 1, 2610, Antwerp, Belgium.
⁹ Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Reed Neurological Research Center, 710 Westwood Plaza, Los Angeles, CA, 90095, USA.
¹⁰ Department of Neurology, Case Western Reserve University, 11100 Euclid Ave, Cleveland, OH, 44106, USA.
¹¹ Department of Neurology, University of North Carolina, 170 Manning Dr, Chapel Hill, NC, 27599, USA.
¹² Department of Neurology, Vanderbilt University, 1161 21St Ave S, Nashville, TN, 37212, USA.
¹³ Department of Neurology, Frontotemporal Disorders Unit, Massachusetts General Hospital and Harvard Medical School, 149 13th St, Boston, MA, 02129, USA.
¹⁴ Department of Neurology, University of Washington, 1959 NE Pacific St, Seattle, WA, 98195-6465, USA.
¹⁵ Department of Neurosciences, University of California, 9500 Gilman Drive, La Jolla, CA, 92037-0948, USA.
¹⁶ Departments of Neurology and Psychiatry, Washington University School of Medicine, Washington University, 660 South Euclid, St. Louis, MO, 63110, USA.
¹⁷ Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
¹⁸ Department of Neurology, Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Northwestern Feinberg School of Medicine, 300 E. Superior, Tarry 8-715, Chicago, IL, 60610, USA.
¹⁹ Center for Neurodegenerative Disease, Department of Neurology, Emory University School of Medicine and Emory, 12 Executive Park Drive, Atlanta, GA, 30329, USA.
²⁰ Division of Neurology, University of British Columbia, S151-2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada.
²¹ Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, 345 Blackstone Boulevard, Providence, RI, 02906, USA.
²² Department of Neurology and Penn Frontotemporal Degeneration Center, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce St, Philadelphia, PA, 19104, USA.
²³ Disorders and Stroke, National Institute of Neurological, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA.
²⁴ Department of Neurosciences, University of California, 9452 Medical Center Drive, La Jolla, CA, 92037, USA.
²⁵ Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada.
²⁶ Department of Neurology, Houston Methodist Neurological Institute, Weill Cornell Medicine, 6560 Fannin St, Houston, TX, 77030, USA.
²⁷ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD, 21287, USA.
²⁸ Department of Neurology, University of Colorado School of Medicine, 12631 East 17Th Avenue, Aurora, CO, 80045, USA.
²⁹ Layton Aging and Alzheimer's Disease Research Center, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
³⁰ Department of Neurology, University of Alabama at Birmingham, 1825 University Blvd, Birmingham, AL, 35233, USA.
³¹ Division of Neurology, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen's Park Crescent West, Third Floor, Toronto, ON, M5S 3H2, Canada.
³² Department of Pathology, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA, 94143, USA.
³³ Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Gendron.Tania@mayo.edu.
³⁴ Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Gendron.Tania@mayo.edu.

PMID: 40075459
PMCID: PMC11905702
DOI: 10.1186/s13024-025-00821-4

Comparative Study

Comprehensive cross-sectional and longitudinal comparisons of plasma glial fibrillary acidic protein and neurofilament light across FTD spectrum disorders

Udit Sheth et al. Mol Neurodegener. 2025.

. 2025 Mar 12;20(1):30.

doi: 10.1186/s13024-025-00821-4.

Authors

Affiliations

¹ Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
² Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
³ Division of Clinical Trials and Biostatistics, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
⁴ Memory and Aging Center, Department of Neurology, University of California San Francisco, 675 Nelson Rising Lane, San Francisco, CA, 91358, USA.
⁵ Department of Neurology, Mayo Clinic, 200 First St, SW, Rochester, MN, 55905, USA.
⁶ Department of Medical and Molecular Genetics, The National Centralized Repository for Alzheimer's Disease and Related Dementias, 351 W. 10Th St TK-217, Indianapolis, IN, 46202, USA.
⁷ Department of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.
⁸ VIB Center for Molecular Neurology, VIB, Universiteitsplein 1, 2610, Antwerp, Belgium.
⁹ Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Reed Neurological Research Center, 710 Westwood Plaza, Los Angeles, CA, 90095, USA.
¹⁰ Department of Neurology, Case Western Reserve University, 11100 Euclid Ave, Cleveland, OH, 44106, USA.
¹¹ Department of Neurology, University of North Carolina, 170 Manning Dr, Chapel Hill, NC, 27599, USA.
¹² Department of Neurology, Vanderbilt University, 1161 21St Ave S, Nashville, TN, 37212, USA.
¹³ Department of Neurology, Frontotemporal Disorders Unit, Massachusetts General Hospital and Harvard Medical School, 149 13th St, Boston, MA, 02129, USA.
¹⁴ Department of Neurology, University of Washington, 1959 NE Pacific St, Seattle, WA, 98195-6465, USA.
¹⁵ Department of Neurosciences, University of California, 9500 Gilman Drive, La Jolla, CA, 92037-0948, USA.
¹⁶ Departments of Neurology and Psychiatry, Washington University School of Medicine, Washington University, 660 South Euclid, St. Louis, MO, 63110, USA.
¹⁷ Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
¹⁸ Department of Neurology, Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Northwestern Feinberg School of Medicine, 300 E. Superior, Tarry 8-715, Chicago, IL, 60610, USA.
¹⁹ Center for Neurodegenerative Disease, Department of Neurology, Emory University School of Medicine and Emory, 12 Executive Park Drive, Atlanta, GA, 30329, USA.
²⁰ Division of Neurology, University of British Columbia, S151-2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada.
²¹ Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, 345 Blackstone Boulevard, Providence, RI, 02906, USA.
²² Department of Neurology and Penn Frontotemporal Degeneration Center, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce St, Philadelphia, PA, 19104, USA.
²³ Disorders and Stroke, National Institute of Neurological, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA.
²⁴ Department of Neurosciences, University of California, 9452 Medical Center Drive, La Jolla, CA, 92037, USA.
²⁵ Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada.
²⁶ Department of Neurology, Houston Methodist Neurological Institute, Weill Cornell Medicine, 6560 Fannin St, Houston, TX, 77030, USA.
²⁷ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD, 21287, USA.
²⁸ Department of Neurology, University of Colorado School of Medicine, 12631 East 17Th Avenue, Aurora, CO, 80045, USA.
²⁹ Layton Aging and Alzheimer's Disease Research Center, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
³⁰ Department of Neurology, University of Alabama at Birmingham, 1825 University Blvd, Birmingham, AL, 35233, USA.
³¹ Division of Neurology, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen's Park Crescent West, Third Floor, Toronto, ON, M5S 3H2, Canada.
³² Department of Pathology, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA, 94143, USA.
³³ Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Gendron.Tania@mayo.edu.
³⁴ Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Gendron.Tania@mayo.edu.

PMID: 40075459
PMCID: PMC11905702
DOI: 10.1186/s13024-025-00821-4

Abstract

Background: Therapeutic development for frontotemporal dementia (FTD) is hindered by the lack of biomarkers that inform susceptibility/risk, prognosis, and the underlying causative pathology. Blood glial fibrillary acidic protein (GFAP) has garnered attention as a FTD biomarker. However, investigations of GFAP in FTD have been hampered by symptomatic and histopathologic heterogeneity and small cohort sizes contributing to inconsistent findings. Therefore, we evaluated plasma GFAP as a FTD biomarker and compared its performance to that of neurofilament light (NfL) protein, a leading FTD biomarker.

Methods: We availed ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study resources to conduct a comprehensive cross-sectional and longitudinal examination of the susceptibility/risk, prognostic, and predictive performance of GFAP and NfL in the largest series of well-characterized presymptomatic FTD mutation carriers and participants with sporadic or familial FTD syndromes. Utilizing single molecule array technology, we measured GFAP and NfL in plasma from 161 controls, 127 presymptomatic mutation carriers, 702 participants with a FTD syndrome, and 67 participants with mild behavioral and/or cognitive changes. We used multivariable linear regression and Cox proportional hazard models adjusted for co-variates to examine the biomarker utility of baseline GFAP and NfL concentrations or their rates of change.

Results: Compared to controls, GFAP and NfL were elevated in each FTD syndrome but GFAP, unlike NfL, poorly discriminated controls from participants with mild symptoms. Similarly, both baseline GFAP and NfL were higher in presymptomatic mutation carriers who later phenoconverted, but NfL better distinguished non-converters from phenoconverters. We additionally observed that GFAP and NfL were associated with disease severity indicators and survival, but NfL far outperformed GFAP. Nevertheless, we validated findings that the GFAP/NfL ratio may discriminate frontotemporal lobar degeneration with tau versus TDP-43 pathology.

Conclusions: Our head-to-head comparison of plasma GFAP and NfL as biomarkers for FTD indicate that NfL consistently outmatched GFAP as a prognostic and predictive biomarker for participants with a FTD syndrome, and as a susceptibility/risk biomarker for people at genetic risk of FTD. Our findings underscore the need to include leading biomarkers in investigations evaluating new biomarkers if the field is to fully ascertain their performance and clinical value.

Keywords: Behavioral variant frontotemporal dementia; Biofluid; Biomarker; Corticobasal syndrome; Glial fibrillary acidic protein; Neurofilament light; Plasma; Presymptomatic; Primary progressive aphasia; Progressive supranuclear palsy-Richardson’s syndrome.

PubMed Disclaimer

Conflict of interest statement

Declarations. Ethics approval and consent to participate: This study involves human participants enrolled through ALLFTD (NCT04363684), and was approved by the Johns Hopkins Medicine Institutional Review Board (IRB) serving as the single IRB for the ALLFTD Consortium (CR00042454/IRB00227492). Participants or their caregivers provided written informed consent. Competing interests: B.S.A. receives research support from the Centers for Disease Control and Prevention, the National Institutes of Health (NIH), Ionis, Alector and the CJD Foundation. He has provided consultation to Acadia, Ionis and Sangamo. B.F.B. has served as an investigator for clinical trials sponsored by Alector, Transposon, EIP Pharma and Cognition Therapeutics. He serves on the Scientific Advisory Board of the Tau Consortium which is funded by the Rainwater Charitable Foundation. He receives research support from NIH. A.L.B. receives research support from the NIH, the Tau Research Consortium, the Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, the GHR Foundation and the Alzheimer’s Association. He has been a consultant for Alchemab, Alector, Alexion, Amylyx, Arrowhead, Arvinas, Eli Lilly, Muna, Neurocrine, Ono, Oscotec, Pfizer, Switch, Transposon, and UnlearnAI. A.C.B. receives research support from the NIH, Cognition Therapeutics and EIP Pharma, serves as a consultant for Creative Biopeptides and Cognition Therapeutics, and serves on the data safety management board of AviadoBio Pharma. B.C.D. is a consultant for Acadia, Alector, Arkuda, Biogen, Denali, Eisai, Genentech, Ilios, Lilly, Merck, Takeda, Wave Lifesciences. He also receives royalties from Cambridge University Press, Elsevier, Oxford University Press. K.D.-R. receives research support from the NIH and served as an investigator for a clinical trial sponsored by Lawson Health Research Institute. T.M.F. receives research support from the NIH. D.R.G. received research funding from the NIH and the Michael J Fox Foundation, served as a paid consultant for Eisai, Fujirebio and GE Healthcare, and serves on a DSMB for Artery Therapeutics. T.F.G. receives research support from the NIH, and is a member of the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium. N.R.G.-R. receives royalties from UpToDate and has participated in multicenter therapy studies by sponsored by Biogen, Eisai, and Lilly. He receives research support from the NIH. I.M.G. served as a site investigator for trials sponsored by Alector, Eisai and Biogen. For some trials for which he was site PI, he received funding from the NIH. C.M.H. is a site principal investigator or sub-investigator for several industry (Alector, Janssen, Biogen, Cogito Tx) sponsored clinical trials with funding through Emory Office of Sponsored Programs and receives funding from NIH. M.G.H. is on the Molecular Neurodegeneration editorial board. H.W.H. receives funding from NIH. G.-Y.R.H. has served as an investigator for clinical trials sponsored by Biogen, Cassava, and Eli Lilly. He receives research support from the Canadian Institutes of Health Research and the Alzheimer Society of British Columbia. E.D.H. receives research support from the NIH (R01AG062268, R01MH120794, U01AG79850). D.I. receives research support from the NIH, as well as Prevail, Passage Bio, Alector and Denali. J.Y.K receives research support from the Intramural Research Program, NINDS, NIH. I.L. is supported by the National Institutes of Health grants: U01NS100610, U01NS80818, R25NS098999; U19 AG063911-1, 1R21NS114764-01A1 and 2 P30 AG062429-06; the Michael J Fox Foundation, Parkinson Foundation, Lewy Body Association, CurePSP, Roche, Abbvie, Biogen, Lundbeck, EIP-Pharma, Novartis, Alterity and UCB. She is a Scientific advisor for Amydis (gratis), Aprinoia, and Rossy Center for Progressive Supranuclear Palsy University of Toronto. She receives her salary from the University of California San Diego and as Chief Editor of Frontiers in Neurology. I.R.M. receives research funding from the Canadian Institutes of Health Research, the Alzheimer’s Association US, the NIH and the Weston Brain Institute. J.C.M. receives grant support from the NIH, and participates in clinical trials sponsored by Biogen and Alector. N.G. has participated or is currently participating in clinical trials of anti-dementia drugs sponsored by Bristol Myers Squibb, Eli Lilly/Avid Radiopharmaceuticals, Janssen Immunotherapy, Novartis, Pfizer, Wyeth, SNIFF (The Study of Nasal Insulin to Fight Forgetfulness) and the A4 (The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease) trial. She receives research support from Tau Consortium and the Association for Frontotemporal Dementia and is funded by the NIH. She serves as a consultant for the Blue Cross Blue Shield Association. LÖ received funding from the Swedish Dementia Foundation. C.U.O. has received research funding from the NIH, Lawton Health Research Institute, National Ataxia Foundation, Alector and Transposon. He is also supported by the Robert and Nancy Hall Brain Research Fund, the Jane Tanger Black Fund for Young-Onset Dementias and a gift from Joseph Trovato. He is a consultant with Alector Inc., Acadia Pharmaceuticals, Reata Pharmaceuticals, Otsuka Pharmaceuticals, Lykos Therapeutics, and Zevra Therapeutics. He serves of the scientific advisory boards of the Tau Consortium and the FTD Disorders Registry. B.P. receives grant support from the NIH, and participates in clinical trials sponsored by Alector. L.P. receives grant support from the NIH and the Association for Frontotemporal Degeneration, and has provided consultation to Expansion Therapeutics. P.S.P. receives research funding from the NIH and has received research support from the Doris Duke Fund to Retain Clinical Scientists. R.R. receives research funding from the NIH and the Bluefield Project to Cure Frontotemporal Dementia. She is on the scientific advisory board of Arkuda Therapeutics and receives royalties from progranulin-related patent. She is also on the scientific advisory board of the Foundation Alzheimer. E.M.R. receives research support from the NIH. E.D.R. has received research support from the NIH, the Bluefield Project to Cure Frontotemporal Dementia, the Alzheimer's Association, the Alzheimer's Drug Discovery Foundation, the BrightFocus Foundation, and Alector; has served as a consultant for AGTC and on a data monitoring committee for Lilly; and owns intellectual property related to tau. H.J.R. has received research support from Eisai Pharmaceuticals and Genentech, and receives research support from the NIH and the state of California. W.W.S has received consulting fees from BridgeBio, Guidepoint Global, Inc., and GLG Council; speaker honoraria from Verge Genomics; and compensation as a member of the scientific advisory board for Lyterian Therapeutics. M.C.T. has served as an investigator for clinical trials sponsored by Biogen, Avanex, Green Valley, Roche/Genentech, Bristol Myers Squibb, Eli Lilly/Avid Radiopharmaceuticals and Janssen. She has served as a consultant for Eli Lilly, and Eisai Pharmaceuticals. She has received research support from Hoffman-Roche. She receives research support from the NIH, Weston Brain Foundation, CurePSP. R.R.D, D.W.D, K.M.F., L.K.F, A.L.L., L.J.W, M.F.M, U.S. and A.S. have nothing to disclose.

Figures

**Fig. 1**
Associations of plasma GFAP and NfL concentrations with age and sex in some phenotype groups. Associations of baseline concentrations of GFAP (a) or NfL (b) with age and sex assessed using linear regression models adjusted for age, sex and, for bvFTD, also for symptom duration. The number of participants (n), β coefficients (β), 95% confidence intervals (95% CI) and p values are shown. p < 0.025 (controls and presymptomatic mutation carriers) or p < 0.017 (bvFTD) are considered statistically significant. Grey circles represent seven bvFTD participants with an unknown mutation status, two bvFTD participants with a *TARDBP* mutation, and one bvFTD participant with a likely *VCP* pathogenic variant. GFAP and NfL concentrations are shown on the base 2 logarithm scale. Black horizontal bars represent median GFAP or NfL concentrations. See also Tables S6 and S7 for associations of baseline GFAP and NfL with age, sex and disease duration in other disease groups

**Fig. 2**
Baseline plasma GFAP and NfL are elevated in FTD syndromes. **a, b** Comparison of baseline plasma GFAP (a) and NfL (b) between healthy controls or presymptomatic mutation carriers and all participants for a given symptomatic group. **c, d** Comparison of baseline GFAP (c) and NfL (d) between controls or presymptomatic carriers and participants in symptomatic groups with a CDR® + NACC-FTLD global score of 0 or 0.5. **a-d** Heat maps show AUCs comparing controls to the indicated groups that either include all individuals (All participants) or only those with an CDR® + NACC-FTLD global score of 0 or 0.5 (Mildly impaired participants) from unadjusted or age and sex-adjusted analyses. The number of participants (n) is shown. p values are from analysis adjusted for age and sex; p < 0.0071 (comparisons to controls) or p < 0.0083 (comparisons to presymptomatics) were considered statistically significant. ****p < 0.0001 and **p < 0.01 (comparison to controls); ^####p < 0.0001, ^###p < 0.001 and ^##p < 0.01 (comparison to presymptomatic mutation carriers). Horizontal bars represent median GFAP or NfL concentrations, which are shown on the base 2 logarithm scale. See Tables S8 and S9 relating to panels a and b, and Tables S14 and S15 relating to panels c and d

**Fig. 3**
GFAP demonstrates less utility as a susceptibility/risk biomarker compared to NfL. **a, b** Comparison of baseline GFAP (a) or NfL (b) concentrations in presymptomatic carriers who phenoconverted to controls or to presymptomatic carriers who remained asymptomatic for at least one year. **c, d** Comparison of baseline GFAP (c) or NfL (d) concentrations in controls to presymptomatic individuals with either a *C9orf72*, *GRN* or *MAPT* mutation. **e, f** Comparison of GFAP (e) or NfL (f) rates of change in presymptomatic carriers who phenoconverted to controls or to presymptomatic carriers who remained asymptomatic for at least one year. g, h Comparison of GFAP (g) or NfL (h) rates of change in controls to presymptomatic individuals with either a *C9orf72*, *GRN* or *MAPT* mutation. The number of participants (n) is shown. p values are from analysis adjusted for age and sex. p < 0.0167 is considered statistically significant. ****p < 0.0001, **p < 0.01 and *p = 0.013 (comparison to controls); ^##p < 0.01 (comparison of phenoconverters to non-converters). In panels **a-d**, horizontal bars represent median GFAP or NfL concentrations, which are shown on the base 2 logarithm scale. In panels **e–h**, rates of GFAP or NfL change are shown with box and whiskers plots representing minimum, first quartile, median, third quartile, and maximum values. See Table S16 relating to panels a, b, e and f, and Table S18 relating to panels c, d, g and h

**Fig. 4**
Rates of GFAP and NfL change across prodromal and symptomatic phases. a,b For individuals with one or more serial GFAP (a) or NfL (b) measurements at least one year from baseline, we show comparisons of rate of change in biomarker concentrations per year for controls, all presymptomatic mutation carriers combined (All PreSx), presymptomatic carriers who did not convert (Non-conv), those that did phenoconvert (Phenoconv) and participants with MBCI, bvFTD, PPA or parkinsonian disorders. The number of participants (n) is shown. p values are from analysis adjusted for age and sex when comparing rates of GFAP or NfL change between controls and the indicated groups. p < 0.0071 is considered statistically significant; ****p < 0.0001, *** p < 0.001 and **p < 0.01. See also Table S19

**Fig. 5**
Plasma NfL better predicts survival after symptom onset than plasma GFAP. Comparisons of baseline GFAP (**a, b**) or NfL (**c, d**) concentrations in predicting survival after symptom onset in participants with bvFTD or in the combined group of participants with a FTD syndrome. For ease of presentation, GFAP and NfL were divided into a 2-level categorical variable based on sample medians. bvFTD, n = 301 (participants who died, n = 42); all FTD syndromes, n = 678 (participants who died, n = 105). In (a): Low ≤ 247.00 pg/ml, High > 247.00 pg/ml. In (b): Low ≤ 237.00 pg/ml, High > 237.00 pg/ml. In (c): Low ≤ 42.00 pg/ml, High > 42.00 pg/ml. In (d) Low ≤ 32.00 pg/ml, High > 32.00 pg/ml. See also Table S26

**Fig. 6**
Baseline NfL and GFAP/NfL ratio can discern FTLD-tau from FTLD-TDP pathology. **a-c** Comparisons of baseline GFAP (a), NfL (b), or GFAP/NfL (c) in the combined group of participants with a FTD syndrome with no mutation, or either a *C9orf72, GRN,* or *MAPT* mutation. p values are from analysis adjusted for age, sex and symptom duration. p < 0.0083 is considered statistically significant; ****p < 0.0001 (comparison to no mutation participants, “None”); ^####p < 0.0001 (comparison to *GRN* mutation carriers). **d-f** Comparisons of GFAP (d), NfL (e), or GFAP/NfL (f) between neuropathologically confirmed participants with FTLD-tau or with FTLD-TDP. p values are from analysis adjusted for age at biomarker measurement, sex, symptom duration, and age at death. p < 0.025 is considered statistically significant; ****p < 0.0001. In all panels, the number of participants (n) is shown, and horizontal bars represent median GFAP, NfL or GFAP/NfL concentrations, which are shown on the base 2 logarithm scale. See Tables S27 and S28 for panels (**a-c**), and Table S29 for panels (**d-f**)

See this image and copyright information in PMC

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Comprehensive cross-sectional and longitudinal comparisons of plasma glial fibrillary acidic protein and neurofilament light across FTD spectrum disorders

Affiliations

Comprehensive cross-sectional and longitudinal comparisons of plasma glial fibrillary acidic protein and neurofilament light across FTD spectrum disorders

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous