Lancet Neurol. 2019 Dec;18(12):1103-1111. doi: 10.1016/S1474-4422(19)30354-0.Serum neurofilamentlight chain in genetic frontotemporal dementia: a longitudinal, multicentre cohort study.
van der Ende EL1, Meeter LH1, Poos JM1, Panman JL2, Jiskoot LC3, Dopper EGP1, Papma JM1, de Jong FJ1, Verberk IMW4, Teunissen C4, Rizopoulos D5, Heller C6, Convery RS6, Moore KM6, Bocchetta M6, Neason M6, Cash DM6, Borroni B7, Galimberti D8, Sanchez-Valle R9, Laforce R Jr10, Moreno F11, Synofzik M12, Graff C13, Masellis M14, Carmela Tartaglia M15, Rowe JB16, Vandenberghe R17, Finger E18, Tagliavini F19, de Mendonça A20, Santana I21, Butler C22, Ducharme S23, Gerhard A24, Danek A25, Levin J26, Otto M27, Frisoni GB28, Cappa S28, Pijnenburg YAL29, Rohrer JD6, van Swieten JC30; Genetic Frontotemporal dementia Initiative (GENFI).Abstract
BACKGROUND:
Neurofilamentlight chain (NfL) is a promising blood biomarker in genetic frontotemporal dementia, with elevated concentrations in symptomatic carriers of mutations in GRN, C9orf72, and MAPT. A better understanding of NfL dynamics is essential for upcoming therapeutic trials. We aimed to study longitudinal NfL trajectories in people with presymptomatic and symptomatic genetic frontotemporal dementia.
METHODS:
We recruited participants from 14 centres collaborating in the Genetic Frontotemporal Dementia Initiative (GENFI), which is a multicentre cohort study of families with genetic frontotemporal dementia done across Europe and Canada. Eligible participants (aged ≥18 years) either had frontotemporal dementia due to a pathogenic mutation in GRN, C9orf72, or MAPT (symptomatic mutation carriers) or were healthy at-risk first-degree relatives (either presymptomatic mutation carriers or non-carriers), and had at least two serum samples with a time interval of 6 months or more. Participants were excluded if they had neurological comorbidities that were likely to affect NfL, including cerebrovascular events. We measured NfL longitudinally in serum samples collected between June 8, 2012, and Dec 8, 2017, through follow-up visits annually or every 2 years, which also included MRI and neuropsychological assessments. Using mixed-effects models, we analysed NfL changes over time and correlated them with longitudinal imaging and clinical parameters, controlling for age, sex, and study site. The primary outcome was the course of NfL over time in the various stages of genetic frontotemporal dementia.
FINDINGS:
We included 59 symptomatic carriers and 149 presymptomatic carriers of a mutation in GRN, C9orf72, or MAPT, and 127 non-carriers. Nine presymptomatic carriers became symptomatic during follow-up (so-called converters). Baseline NfL was elevated in symptomatic carriers (median 52 pg/mL [IQR 24-69]) compared with presymptomatic carriers (9 pg/mL [6-13]; p<0·0001) and non-carriers (8 pg/mL [6-11]; p<0·0001), and was higher in converters than in non-converting carriers (19 pg/mL [17-28] vs 8 pg/mL [6-11]; p=0·0007; adjusted for age). During follow-up, NfL increased in converters (b=0·097 [SE 0·018]; p<0·0001). In symptomatic mutation carriers overall, NfL did not change during follow-up (b=0·017 [SE 0·010]; p=0·101) and remained elevated. Rates of NfL change over time were associated with rate of decline in Mini Mental State Examination (b=-94·7 [SE 33·9]; p=0·003) and atrophy rate in several grey matter regions, but not with change in Frontotemporal Lobar Degeneration-Clinical Dementia Rating scale score (b=-3·46 [SE 46·3]; p=0·941).
INTERPRETATION:
Our findings show the value of blood NfL as a disease progression biomarker in genetic frontotemporal dementia and suggest that longitudinal NfL measurements could identify mutation carriers approaching symptom onset and capture rates of brain atrophy. The characterisation of NfL over the course of disease provides valuable information for its use as a treatment effect marker.
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