Abstract
Objective: We tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk of disease progression. Methods: Baseline plasma NfL concentrations were measured with single-molecule array in original (n = 277) and validation (n = 297) cohorts. C9orf72, GRN, and MAPT mutation carriers and noncarriers from the same families were classified by disease severity (asymptomatic, prodromal, and full phenotype) using the CDR Dementia Staging Instrument plus behavior and language domains from the National Alzheimer's Disease Coordinating Center FTLD module (CDR+NACC-FTLD). Linear mixed-effect models related NfL to clinical variables. Results: In both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to nonprogressors (original: 11.4 ± 7 pg/mL vs 6.7 ± 5 pg/mL, p = 0.002; validation: 14.1 ± 12 pg/mL vs 8.7 ± 6 pg/mL, p = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or those with prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR+NACC-FTLD sum of boxes scores, neuropsychological function, and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers. Conclusions: Plasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression and is a potential tool to select participants for prevention clinical trials.
Original language | English (US) |
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Pages (from-to) | E2296-E2312 |
Journal | Neurology |
Volume | 96 |
Issue number | 18 |
DOIs | |
State | Published - May 4 2021 |
Funding
ALLFTD Consortium (LEFFTDS: U01 AG045390; ARTFL: U54 NS092089; ALLFTD: U19AG063911). J.C.R. is supported by National Institute on Aging-NIH: K23AG059888. AMS is supported by National Institute on Aging-NIH: K23AG061253 and Larry L. Hillblom Foundation: 2018-A- 025-FEL. Work was also supported by grants U24 AG021886 and U01 AG016976 and the Bluefield Project to Cure FTD. Samples from the National Centralized Repository for Alzheimer's Disease and Related Dementias, which receives government support under a cooperative agreement grant (U24 AG21886), were used in this study. The Dementia Research Centre is supported by Alzheimer's Research UK, Alzheimer's Society, Brain Research UK, and The Wolfson Foundation. This work was supported by the National Institute for Health Research UCL/H Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre Clinical Research Facility, and the UK Dementia Research Institute, which receives its funding fromUKDRI Ltd, funded by the UKMedical Research Council, Alzheimer's Society, and Alzheimer's Research UK. J.D.R. is supported by a Medical Research Council Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the National Institute for Health Research Rare Disease Translational Research Collaboration (BRC149/ NS/MH). R.C. and C.G. are supported by Frontotemporal Dementia Research Studentships in Memory of David Blechner funded through The National Brain Appeal (RCN 290173). M.B. is supported by a Fellowship award from the Alzheimer's Society, UK (AS-JF-19a-004-517) and by the UK Dementia Research Institute, which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society, and Alzheimer's Research UK. R.L. is supported by the Canadian Institutes of Health Research and the Chaire de Recherche sur les Aphasies Primaires Progressives Fondation Famille Lemaire. C.G. is supported by the Swedish Frontotemporal Dementia Initiative Sch\u00A8orling Foundation, Swedish Research Council, JPND Prefrontals, 2015-02926, 2018-02754, Swedish Alzheimer Foundation, Swedish Brain Foundation, Karolinska Institutet Doctoral Funding, KI Strat- Neuro, SwedishDementia Foundation, and StockholmCounty Council ALF/Region Stockholm. J.L. is supported by Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (German Research Foundation, EXC 2145 SyNergy 390857198). This work was also supported by the Medical Research Council UK GENFI grant (MR/M023664/1), the Bluefield Project, the National Institute for Health Research including awards to Cambridge and UCL Biomedical Research Centres, and the JPND GENFI-PROX grant (2019-02248). Several authors of this publication are members of the European Reference Network for Rare Neurologic Diseases, project No. 739510. J.B.R. is supported by NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). ALLFTD Consortium (LEFFTDS: U01 AG045390; ARTFL: U54 NS092089; ALLFTD: U19AG063911). J.C.R. is supported by National Institute on Aging\u2013NIH: K23AG059888. AMS is supported by National Institute on Aging\u2013NIH: K23AG061253 and Larry L. Hillblom Foundation: 2018-A-025-FEL. Work was also supported by grants U24 AG021886 and U01 AG016976 and the Bluefield Project to Cure FTD. Samples from the National Centralized Repository for Alzheimer\u2019s Disease and Related Dementias, which receives government support under a cooperative agreement grant (U24 AG21886), were used in this study. The Dementia Research Centre is supported by Alzheimer's Research UK, Alzheimer's Society, Brain Research UK, and The Wolfson Foundation. This work was supported by the National Institute for Health Research UCL/H Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre Clinical Research Facility, and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society, and Alzheimer's Research UK. J.D.R. is supported by a Medical Research Council Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the National Institute for Health Research Rare Disease Translational Research Collaboration (BRC149/NS/MH). R.C. and C.G. are supported by Frontotemporal Dementia Research Studentships in Memory of David Blechner funded through The National Brain Appeal (RCN 290173). M.B. is supported by a Fellowship award from the Alzheimer\u2019s Society, UK (AS-JF-19a-004-517) and by the UK Dementia Research Institute, which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer\u2019s Society, and Alzheimer\u2019s Research UK. R.L. is supported by the Canadian Institutes of Health Research and the Chaire de Recherche sur les Aphasies Primaires Progressives Fondation Famille Lemaire. C.G. is supported by the Swedish Frontotemporal Dementia Initiative Sch\u00F6rling Foundation, Swedish Research Council, JPND Prefrontals, 2015\u201302926, 2018\u201302754, Swedish Alzheimer Foundation, Swedish Brain Foundation, Karolinska Institutet Doctoral Funding, KI StratNeuro, Swedish Dementia Foundation, and Stockholm County Council ALF/Region Stockholm. J.L. is supported by Germany\u2019s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (German Research Foundation, EXC 2145 SyNergy 390857198). This work was also supported by the Medical Research Council UK GENFI grant (MR/M023664/1), the Bluefield Project, the National Institute for Health Research including awards to Cambridge and UCL Biomedical Research Centres, and the JPND GENFI-PROX grant (2019\u201302248). Several authors of this publication are members of the European Reference Network for Rare Neurologic Diseases, project No. 739510. J.B.R. is supported by NIHR Cambridge Biomedical Research Centre (BRC-1215-20014).
ASJC Scopus subject areas
- Clinical Neurology