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

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.

High serum neurofilament associates with diffuse white matter damage in MS

“…Accordingly, in other neurologic disease with brain diffuse pathology such as amyotrophic lateral sclerosis, Alzheimer disease, traumatic brain injury, and age-related white matter pathology, elevated serum NfL levels have been associated with DTI-measurable diffuse damage within the CNS. 25 – 28 These studies are further evidence for the concept that brain diffuse, chronic neuropathologic mechanisms contribute to NfL release and that nonconventional MRI techniques are able to identify the CNS areas of its morphologic source.…”

“…To explore associations between increased NfL levels and DTImeasurable diffuse neuroaxonal damage, patients with MS were divided into NfL(high) and NfL(low) subgroups. The division was based on the median NfL value measured among healthy controls (23.1 [21][22][23][24][25][26][27][28] pg/mL). In the NfL(high) subgroup, the NfL concentration was significantly elevated compared with healthy controls (p = 0.018, table 1), and in the further NfL vs DTI correlation analyses, we focused on the NfL(high) subgroup.…”

Plasma neurofilament light and cerebrospinal fluid biomarkers are associated with white matter damage in Alzheimer's disease

“…Crucially, these signature regions are involved in the pathological course of Alzheimer's disease, and alterations in white matter integrity in these regions are known to be associated with disease progression from the early stages of AD (14). Also, serum level of NFL correlates with lower FA and Higher RD, AD, and MD in autosomal dominant Alzheimer's disease (15,16). By investigating diffusion metrics, information about the different speci cations of the White matter can be obtained from DTI values.…”

Plasma neurofilament light is associated with white matter damage in Alzheimer's disease

“…Crucially, these signature regions are involved in the white matter changes due to Alzheimer's disease, and alterations in white matter integrity in these regions are known to be associated with disease progression from the early stages of AD (20). Also, the serum level of NFL correlates with lower FA and higher RD, DA, and MD in autosomal dominant Alzheimer's disease (21,22).…”