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. 2020 Aug:142:104960.
doi: 10.1016/j.nbd.2020.104960. Epub 2020 Jun 6.

Serum neurofilament light chain levels are associated with white matter integrity in autosomal dominant Alzheimer's disease

Stephanie A Schultz  1 , Jeremy F Strain  1 , Adedamola Adedokun  1 , Qing Wang  1 , Oliver Preische  2 , Jens Kuhle  3 , Shaney Flores  1 , Sarah Keefe  1 , Aylin Dincer  1 , Beau M Ances  1 , Sarah B Berman  4 , Adam M Brickman  5 , David M Cash  6 , Jasmeer Chhatwal  7 , Carlos Cruchaga  1 , Michael Ewers  8 , Nick N Fox  9 , Bernardino Ghetti  10 , Alison Goate  11 , Neill R Graff-Radford  12 , Jason J Hassenstab  1 , Russ Hornbeck  1 , Clifford Jack Jr  13 , Keith Johnson  7 , Nelly Joseph-Mathurin  1 , Celeste M Karch  1 , Robert A Koeppe  14 , Athene K W Lee  15 , Johannes Levin  16 , Colin Masters  17 , Eric McDade  1 , Richard J Perrin  1 , Christopher C Rowe  18 , Stephen Salloway  19 , Andrew J Saykin  20 , Reisa Sperling  7 , Yi Su  21 , Victor L Villemagne  18 , Jonathan Vöglein  16 , Michael Weiner  22 , Chengjie Xiong  1 , Anne M Fagan  1 , John C Morris  1 , Randall J Bateman  1 , Tammie L S Benzinger  1 , Mathias Jucker  2 , Brian A Gordon  23 ; Dominantly Inherited Alzheimer Network
Affiliations

Serum neurofilament light chain levels are associated with white matter integrity in autosomal dominant Alzheimer's disease

Stephanie A Schultz et al. Neurobiol Dis. 2020 Aug.

Abstract

Neurofilament light chain (NfL) is a protein that is selectively expressed in neurons. Increased levels of NfL measured in either cerebrospinal fluid or blood is thought to be a biomarker of neuronal damage in neurodegenerative diseases. However, there have been limited investigations relating NfL to the concurrent measures of white matter (WM) decline that it should reflect. White matter damage is a common feature of Alzheimer's disease. We hypothesized that serum levels of NfL would associate with WM lesion volume and diffusion tensor imaging (DTI) metrics cross-sectionally in 117 autosomal dominant mutation carriers (MC) compared to 84 non-carrier (NC) familial controls as well as in a subset (N = 41) of MC with longitudinal NfL and MRI data. In MC, elevated cross-sectional NfL was positively associated with WM hyperintensity lesion volume, mean diffusivity, radial diffusivity, and axial diffusivity and negatively with fractional anisotropy. Greater change in NfL levels in MC was associated with larger changes in fractional anisotropy, mean diffusivity, and radial diffusivity, all indicative of reduced WM integrity. There were no relationships with NfL in NC. Our results demonstrate that blood-based NfL levels reflect WM integrity and supports the view that blood levels of NfL are predictive of WM damage in the brain. This is a critical result in improving the interpretability of NfL as a marker of brain integrity, and for validating this emerging biomarker for future use in clinical and research settings across multiple neurodegenerative diseases.

Keywords: Alzheimer's disease; Blood-based biomarkers; Neurodegeneration; Neurofilament; Neuroimaging; White matter.

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Conflict of interest statement

Declaration of competing interest A.M.G. has consulted for Cognition Therapeutics, Biogen, GSK, Illumina, Eisai, AbbVie and Pfizer and served on the SAB for Denali Therapeutics.

Figures

Fig. 1
Fig. 1
Relationship between serum NfL and total white matter hyperintensity volume in mutation carriers. Scatterplot showing the relationship between total WMH volume and serum NfL in MC (n = 117). The shaded area around the linear fit line represents one standard error of the mean from the LME model.
Fig. 2
Fig. 2
Main Effect of serum NfL on DTI metrics in MC. p-Value map (red-yellow) of statistically significant voxel-wise associations of higher NfL and (A) lower fractional anisotropy, (B) higher mean diffusivity, (C) higher axial diffusivity, and (D) higher radial diffusivity superimposed on the white matter skeleton (blue), within mutation carriers (n = 117). Familywise error-corrected at p = .05. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 3
Fig. 3
Tract-specific white matter measures are associated with serum NfL in MC. Scatterplots depicting the relationship between serum NfL and DTI metrics from FA, MD, DA, and DR within three representative ROIs (PCC, SLF, and CST) in MC (n = 117). The shaded area around each linear fit line represents one SE from LME models. FA = fractional anisotropy; MD = mean diffusivity; DA = axial diffusivity; DR = radial diffusivity; PCC = posterior corpus callosum; SLF = superior longitudinal fasciculus; CST = corticospinal tract; NfL = neurofilament light chain; DTI = diffusion tensor imaging; ROIs = regions of interest; MC = mutation carriers; SE = standard error.
Fig. 4
Fig. 4
Longitudinal relationship between serum NfL and WMH in MC. Scatterplot showing the relationship between the estimated annual rate of change in total WMH volume and the estimated annual rate of change in NfL in MC (n = 41). The shaded area around the linear fit line represents one SE from the LME model. NfL = neurofilament light chain; WMH = white matter hyperintensity; ROIs = regions of interest; MC = mutation carriers; SE = standard error.
Fig. 5
Fig. 5
Longitudinal relationship between NfL and DTI metrics in PCC. Scatterplot showing the relationship between the estimated annual rate of change in serum NfL and the estimated annual rate of change in (A) FA in PCC, (B) MD in PCC, (C) DA in PCC, and (D) DR in PCC in MC (n = 41). The shaded area around each linear fit line represents one SE from LME models. FA = fractional anisotropy; MD = mean diffusivity; DA = axial diffusivity; DR = radial diffusivity; PCC = posterior corpus callosum; NfL = neurofilament light chain; DTI = diffusion tensor imaging; SE = standard error.
See this image and copyright information in PMC

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