Back ground Neurofilament light chain (NfL) is a promising blood biomarker in genetic frontotemporal dementia, with elevated concentrations in symptomatic carriers of mutations in GRN, C9orf72, and... Show moreBack ground Neurofilament light 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 Nil 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 [S E 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. Copyright (C) 2019 Elsevier Ltd. All rights reserved. Show less
Beek, M. van de; Steenoven, I. van; Ramakers, I.H.G.B.; Aalten, P.; Koek, H.L.; Rikkert, M.G.M.O.; ... ; Flier, W.M. van der 2019
Background: Quality of Life (QoL) is an important outcome measure in dementia, particularly in the context of interventions. Research investigating longitudinal QoL in dementia with Lewy bodies ... Show moreBackground: Quality of Life (QoL) is an important outcome measure in dementia, particularly in the context of interventions. Research investigating longitudinal QoL in dementia with Lewy bodies (DLB) is currently lacking.Objective: To investigate determinants and trajectories of QoL in DLB compared to Alzheimer's disease (AD) and controls.Methods: QoL was assessed annually in 138 individuals, using the EQ5D-utility-score (0-100) and the health-related Visual Analogue Scale (VAS, 0-100). Twenty-nine DLB patients (age 69 +/- 6), 68 AD patients (age 70 +/- 6), and 41 controls (age 70 +/- 5) were selected from the Dutch Parelsnoer Institute-Neurodegenerative diseases and Amsterdam Dementia Cohort. We examined clinical work-up over time as determinants of QoL, including cognitive tests, neuropsychiatric inventory, Geriatric Depression Scale (GDS), and disability assessment of dementia (DAD).Results: Mixed models showed lower baseline VAS-scores in DLB compared to AD and controls (AD: beta +/- SE = - 7.6 +/- 2.8, controls: beta +/- SE = -7.9 +/- 3.0, p < 0.05). An interaction between diagnosis and time since diagnosis indicated steeper decline on VAS-scores for AD patients compared to DLB patients (beta +/- SE = 2.9 +/- 1.5, p < 0.1). EQ5D-utility-scores over time did not differ between groups. Higher GDS and lower DAD-scores were independently associated with lower QoL in dementia patients (GDS: VAS beta +/- SE = -1.8 +/- 0.3, EQ5D-utility beta +/- SE = -3.7 +/- 0.4; DAD: VAS = 0.1 +/- 0.0, EQ5D-utility beta +/- SE = 0.1 +/- 0.1, p < 0.05). No associations between cognitive tests and QoL remained in the multivariate model.Conclusion: QoL is lower in DLB, while in AD QoL shows steeper decline as the disease advances. Our results indicate that non-cognitive symptoms, more than cognitive symptoms, are highly relevant as they impact QoL. Show less
