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Plasma NfL levels and longitudinal change rates in C9orf72 and GRN-associated diseases: from tailored references to clinical applications
- Source :
- Journal of Neurology, Neurosurgery and Psychiatry, Journal of Neurology, Neurosurgery and Psychiatry, BMJ Publishing Group, In press, ⟨10.1136/jnnp-2021-326914⟩, Journal of Neurology, Neurosurgery and Psychiatry, 2021, 92 (12), pp.1278-1288. ⟨10.1136/jnnp-2021-326914⟩
- Publication Year :
- 2021
- Publisher :
- HAL CCSD, 2021.
-
Abstract
- ObjectiveNeurofilament light chain (NfL) is a promising biomarker in genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We evaluated plasma neurofilament light chain (pNfL) levels in controls, and their longitudinal trajectories in C9orf72 and GRN cohorts from presymptomatic to clinical stages.MethodsWe analysed pNfL using Single Molecule Array (SiMoA) in 668 samples (352 baseline and 316 follow-up) of C9orf72 and GRN patients, presymptomatic carriers (PS) and controls aged between 21 and 83. They were longitudinally evaluated over a period of >2 years, during which four PS became prodromal/symptomatic. Associations between pNfL and clinical–genetic variables, and longitudinal NfL changes, were investigated using generalised and linear mixed-effects models. Optimal cut-offs were determined using the Youden Index.ResultspNfL levels increased with age in controls, from ~5 to~18 pg/mL (pGRN patients had higher levels than C9orf72 (86.21 vs 39.49 pg/mL, p=0.014), and greater progression rates (ARC:+29.3% vs +24.7%; p=0.016). In C9orf72 patients, levels were associated with the phenotype (ALS: 71.76 pg/mL, FTD: 37.16, psychiatric: 15.3; p=0.003) and remarkably lower in slowly progressive patients (24.11, ARC: +2.5%; p=0.05). Mean ARC was +3.2% in PS and +7.3% in prodromal carriers. We proposed gene-specific cut-offs differentiating patients from controls by decades.ConclusionsThis study highlights the importance of gene-specific and age-specific references for clinical and therapeutic trials in genetic FTD/ALS. It supports the usefulness of repeating pNfL measurements and considering ARC as a prognostic marker of disease progression.Trial registration numbersNCT02590276 and NCT04014673.
- Subjects :
- Oncology
0303 health sciences
medicine.medical_specialty
business.industry
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
Disease progression
Youden's J statistic
[SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
medicine.disease
Therapeutic trial
03 medical and health sciences
Psychiatry and Mental health
0302 clinical medicine
C9orf72
Internal medicine
Medicine
Biomarker (medicine)
Surgery
Neurology (clinical)
Amyotrophic lateral sclerosis
business
Trial registration
030217 neurology & neurosurgery
030304 developmental biology
Frontotemporal dementia
Subjects
Details
- Language :
- English
- ISSN :
- 00223050 and 1468330X
- Database :
- OpenAIRE
- Journal :
- Journal of Neurology, Neurosurgery and Psychiatry, Journal of Neurology, Neurosurgery and Psychiatry, BMJ Publishing Group, In press, ⟨10.1136/jnnp-2021-326914⟩, Journal of Neurology, Neurosurgery and Psychiatry, 2021, 92 (12), pp.1278-1288. ⟨10.1136/jnnp-2021-326914⟩
- Accession number :
- edsair.doi.dedup.....ad3c659bea32b6c6df39c83042a56ce7