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. 2019 Sep;90(9):997-1004.
doi: 10.1136/jnnp-2018-319784. Epub 2019 May 23.

Clinical value of cerebrospinal fluid neurofilament light chain in semantic dementia

Lieke H H Meeter  1 , Rebecca M E Steketee  2 , Dina Salkovic  1 , Maartje E Vos  1 , Murray Grossman  3 , Corey T McMillan  3 , David J Irwin  3 , Adam L Boxer  4 , Julio C Rojas  4 , Nicholas T Olney  5 , Anna Karydas  5 , Bruce L Miller  4 , Yolande A L Pijnenburg  6 , Frederik Barkhof  7   8 , Raquel Sánchez-Valle  9   10 , Albert Lladó  9   10 , Sergi Borrego-Ecija  9   10 , Janine Diehl-Schmid  11 , Timo Grimmer  11 , Oliver Goldhardt  11 , Alexander F Santillo  12 , Oskar Hansson  12 , Susanne Vestberg  13 , Barbara Borroni  14 , Alessandro Padovani  14 , Daniela Galimberti  15   16 , Elio Scarpini  15   17 , Jonathan D Rohrer  18 , Ione O C Woollacott  18 , Matthis Synofzik  19   20 , Carlo Wilke  19   20 , Alexandre de Mendonca  21 , Rik Vandenberghe  22   23 , Luisa Benussi  24 , Roberta Ghidoni  24 , Giuliano Binetti  24   25 , Wiro J Niessen  26   27 , Janne M Papma  1 , Harro Seelaar  1 , Lize C Jiskoot  1 , Frank Jan de Jong  1 , Laura Donker Kaat  1   28 , Marta Del Campo  29 , Charlotte E Teunissen  29 , Esther E Bron  26 , Esther Van den Berg  1 , John C Van Swieten  30
Affiliations

Clinical value of cerebrospinal fluid neurofilament light chain in semantic dementia

Lieke H H Meeter et al. J Neurol Neurosurg Psychiatry. 2019 Sep.

Abstract

Background: Semantic dementia (SD) is a neurodegenerative disorder characterised by progressive language problems falling within the clinicopathological spectrum of frontotemporal lobar degeneration (FTLD). The development of disease-modifying agents may be facilitated by the relative clinical and pathological homogeneity of SD, but we need robust monitoring biomarkers to measure their efficacy. In different FTLD subtypes, neurofilament light chain (NfL) is a promising marker, therefore we investigated the utility of cerebrospinal fluid (CSF) NfL in SD.

Methods: This large retrospective multicentre study compared cross-sectional CSF NfL levels of 162 patients with SD with 65 controls. CSF NfL levels of patients were correlated with clinical parameters (including survival), neuropsychological test scores and regional grey matter atrophy (including longitudinal data in a subset).

Results: CSF NfL levels were significantly higher in patients with SD (median: 2326 pg/mL, IQR: 1628-3593) than in controls (577 (446-766), p<0.001). Higher CSF NfL levels were moderately associated with naming impairment as measured by the Boston Naming Test (rs =-0.32, p=0.002) and with smaller grey matter volume of the parahippocampal gyri (rs =-0.31, p=0.004). However, cross-sectional CSF NfL levels were not associated with progression of grey matter atrophy and did not predict survival.

Conclusion: CSF NfL is a promising biomarker in the diagnostic process of SD, although it has limited cross-sectional monitoring or prognostic abilities.

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Conflict of interest statement

Competing interests: The authors report no conflicts of interest relevant to this study. LHHM is supported by Alzheimer Nederland (grant number WE.09 2014 04). ALB and JCR are supported by the NIH (U54NS092089, R01AG031278, R01AG038791, R01AG032306, R01AG022983) and the Association for Frontotemporal Degeneration. ALB, JCR and LDK are supported by the Bluefield Project to Cure Frontotemporal Dementia. The Dementia Research Centre is supported by Alzheimer’s Research UK, Brain Research Trust and The Wolfson Foundation. This work was supported by the NIHR Queen Square Dementia Biomedical Research Unit, the NIHR UCL/H Biomedical Research Centre and the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility as well as an Alzheimer’s Society grant (AS-PG-16-007). JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). IOCW is supported by an MRC Clinical Research Training Fellowship (MR/M018288/1). AS is supported by the Swedish Society for Medical Research. CET is supported by ZonMW Memorabel Program (grant number 733050206). JCvS is supported by the Dioraphte Foundation.

Figures

Figure 1
Figure 1
Flowchart of patients with SD included and excluded per analysis. In total, 162 patients with SD were studied after exclusion of six patients with a CSF profile suggestive of Alzheimer’s disease, of which 87 were included in the cross-sectional imaging associations and 32 in the longitudinal imaging associations; reasons for exclusion are displayed in the upper boxes. The number of patients included in the associations with cognitive screeners and neuropsychological tests is displayed in the lower boxes; this is based on the availability of these measures within 6 months of CSF sampling. BNT, Boston Naming Test; CDR, Clinical Dementia Rating scale; CDR-SB, CDR-sum of boxes; CSF, cerebrospinal fluid; FTD, frontotemporal dementia; MMSE, Mini-Mental State Examination; SCWT, Stroop Color-Word Task; SD, semantic dementia; TMT, Trail-making Test.
Figure 2
Figure 2
CSF NfL concentrations in patients with SD and controls. The horizontal lines represent the median per group. CSF, cerebrospinal fluid; NfL, neurofilament light chain; SD, semantic dementia; ***p<0.001.
Figure 3
Figure 3
Relationship of CSF NfL with language impairment, parahippocampal atrophy and survival in patients with SD. (A) Association between NfL and the BNT as measure for naming impairment. When the patient (who had a right dominant SD) with a high BNT score was excluded, the analyses remained significant. (B) Association between NfL and grey matter volume of the parahippocampal gyrus at the dominant side, displayed as percentage of ICV. (C) NfL was not associated with survival after CSF collection in SD as exemplified by this Kaplan-Meier curve of NfL levels stratified to lowest (green line), middle (blue line) and highest tertiles (red line). Vertical ticks represent living patients. BNT, Boston Naming test; CSF, cerebrospinal fluid; ICV, intracranial volume; NfL, neurofilament light chain; SD, semantic dementia.
Figure 4
Figure 4
Temporal pole atrophy in patients. Transversal T1-weighted MR images of patients representative for the distribution of dominant anterior temporal pole atrophy within the sample. From left to right: patient with lower quartile (A), median (B) and upper quartile (C) anterior temporal pole grey matter volumes of the dominant side.
See this image and copyright information in PMC

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