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.
Highlights
Neurodegenerative disease biomarkers have important roles in defining disease presence and severity, predicting progression, and monitoring disease-modifying therapies
When evaluating whether the relationship between Neurofilament light chain (NfL) and WM hyperintensity (WMH) remained after accounting for a global diffusion tensor imaging (DTI) mean diffusivity (MD) measure we found the relationship between
NfL is thought to reflect damage to large myelinated axons there is a paucity of work systematically examining how NfL levels relate to established markers of macrostructural and microstructural white matter (WM) damage
Summary
Neurodegenerative disease biomarkers have important roles in defining disease presence and severity, predicting progression, and monitoring disease-modifying therapies. The relatively predictable age of dementia onset in ADAD means that one can align asymptomatic individuals relative to their estimated disease onset This makes it possible to investigate decades' worth of the disease course from large cross-sectional samples. Such studies of ADAD have shown that CSF and blood NfL levels are elevated in symptomatic individuals and begin to increase 10–20 years before symptom onset (Preische et al, 2019; Sánchez-Valle et al, 2018; Weston et al, 2017), consistent with the notion that WM damage is an early event in AD.
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