期刊
NEUROLOGY
卷 96, 期 18, 页码 E2296-E2312出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/WNL.0000000000011848
关键词
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资金
- ALLFTD Consortium [LEFFTDS: U01 AG045390, ARTFL: U54 NS092089, ALLFTD: U19AG063911]
- National Institute on Aging-NIH [K23AG059888, K23AG061253]
- Larry L. Hillblom Foundation [2018-A025-FEL]
- Bluefield Project to Cure FTD
- Alzheimer's Research UK
- Alzheimer's Society
- Brain Research UK
- Wolfson Foundation
- National Institute for Health Research UCL/H Biomedical Research Centre
- Leonard Wolfson Experimental Neurology Centre Clinical Research Facility
- UK Dementia Research Institute from UKDRI Ltd - UK Medical Research Council
- Medical Research Council Clinician Scientist Fellowship [MR/M008525/1]
- National Institute for Health Research Rare Disease Translational Research Collaboration [BRC149/ NS/MH]
- Frontotemporal Dementia Research Studentships in Memory of David Blechner through The National Brain Appeal [RCN 290173]
- Alzheimer's Society, UK [AS-JF-19a-004-517]
- UK Dementia Research Institute from DRI Ltd - UK Medical Research Council
- Canadian Institutes of Health Research
- Chaire de Recherche sur les Aphasies Primaires Progressives Fondation Famille Lemaire
- Swedish Frontotemporal Dementia Initiative Schorling Foundation
- Swedish Research Council
- JPND Prefrontals [2015-02926, 2018-02754]
- Swedish Alzheimer Foundation
- Swedish Brain Foundation
- Karolinska Institutet Doctoral Funding
- KI StratNeuro
- SwedishDementia Foundation
- StockholmCounty Council
- ALF/Region Stockholm
- Germany's Excellence Strategy (German Research Foundation) [EXC 2145 SyNergy 390857198]
- Medical Research Council UK GENFI grant [MR/M023664/1]
- Bluefield Project
- National Institute for Health Research
- JPND GENFI-PROX grant [2019-02248]
- European Reference Network for Rare Neurologic Diseases [739510]
- NIHR Cambridge Biomedical Research Centre [BRC-1215-20014]
- [U24 AG021886]
- [U01 AG016976]
- [U24 AG21886]
Plasma neurofilament light chain (NfL) can identify asymptomatic carriers of FTLD-causing mutations at risk of disease progression, providing potential for selecting participants in prevention clinical trials.
ObjectiveWe 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.MethodsBaseline 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.ResultsIn both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to nonprogressors (original: 11.4 & PLUSMN; 7 pg/mL vs 6.7 & PLUSMN; 5 pg/mL, p = 0.002; validation: 14.1 & PLUSMN; 12 pg/mL vs 8.7 & PLUSMN; 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.ConclusionsPlasma 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.Trial Registration InformationClinicalTrials.gov Identifier: NCT02372773 and NCT02365922.Classification of EvidenceThis study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.
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