Cerebrospinal fluid β-amyloid42 and neurofilament light relate to white matter hyperintensities

Abstract

White matter hyperintensities (WMHs) are associated with poorer brain health, but their pathophysiological substrates remain elusive. To better understand the mechanistic underpinnings of WMHs among older adults, this study examined in vivo cerebrospinal fluid biomarkers of β-amyloid₄₂ deposition (Aβ₄₂), hyperphosphorylated tau pathology, neurodegeneration (total tau), and axonal injury (neurofilament light [NFL]) in relation to log-transformed WMHs volume. Participants free of clinical stroke and dementia were drawn from the Vanderbilt Memory & Aging Project (n = 148, 72 ± 6 years). Linear regression models adjusted for age, sex, race/ethnicity, education, intracranial volume, modified Framingham Stroke Risk Profile (excluding points assigned for age), cognitive diagnosis, and APOE-ε4 carrier status. Aβ₄₂ (β = -0.001, p = 0.007) and NFL (β = 0.0003, p = 0.01) concentrations related to WMHs but neither hyperphosphorylated tau nor total tau associations with WMHs reached statistical significance (p-values > 0.21). In a combined model, NFL accounted for 3.2% of unique variance in WMHs and Aβ₄₂ accounted for an additional 4.3% beyond NFL, providing novel evidence of the co-occurrence of at least 2 distinct pathways for WMHs among older adults, including amyloid deposition and axonal injury.

Keywords: Amyloid; Cerebrospinal fluid; Dementia; Neurofilament light; White matter hyperintensities; β-amyloid(42).

Figure 1. Pathophysiology Associated with CSF Biomarkers

Depictions of pathophysiology associated with each CSF biomarker of interest: (1) Aβ₄₂ is a peptide made up of 42 amino acids, which results from cleavage of the amyloid precursor protein by beta and gamma secretase, forming larger peptide chains than its alpha secretase pathway. These larger peptides misfold into oligomers that form the amyloid plaques characteristic of AD. Panel A depicts effective clearance of smaller amyloid peptides through perivascular basement membranes. Panel B depicts impaired clearance of large Aβ peptides corresponding to increased amyloid deposition in the brain, resulting in Aβ oligomers in the extracellular matrix and lower concentrations of Aβ₄₂ in the CSF. (2) Tau is a protein found on microtubules that form the intracellular neurofibrillary tangles characteristic of AD. Higher CSF concentrations of tau occur in response to neurodegeneration. Hyperphosphorylated tau (p-tau) is measured by marking a specific phosphorylation site on the tau protein. P-tau measurements are more specific to Alzheimer’s pathology than total tau due to the hyperphosphorylation of tau that occurs in AD. As depicted on Panel A, tau may be phosphorylated in its normal state and is involved in the dynamic instability of microtubules. Panel B illustrates how tau proteins become hyperphosphorylated in AD, causing tau to prematurely detach from microtubules and disrupt the balance of assembly and disassembly of microtubules. (3) Neurofilament light (NFL) is the smallest and most abundant of three polypeptides that form neurofilament proteins found in large-caliber, myelinated axons. As depicted in Panel A, neurofilaments exist in the axon alongside microtubules, increasing the axon’s diameter and conduction velocity. When axonal damage occurs as illustrated in Panel B, neurofilaments spill into extracellular space and are cleared as cellular waste into the CSF. Higher CSF concentrations of NFL reflect the acute occurrence of axonal injury.

Figure 2. Participant Inclusion/Exclusion Details

Missing data categories are mutually exclusive. CSF=cerebrospinal fluid; FSRP=Framingham Stroke Risk Profile

Figure 3. CSF Biomarker Concentrations of Amyloid-β₄₂ & Neurofilament Light in Association with White Matter Hyperintensities

A. Amyloid-β₄₂ & White Matter Hyperintensities Solid black line reflects unadjusted values of CSF Aβ₄₂ biomarker concentration (X axis) corresponding to WMH volume (Y axis) for illustration purposes only. When covarying for age, sex, race/ethnicity, education, intracranial volume, cognitive diagnosis, and APOE4, Aβ₄₂ related to WMH (β=−0.001, p=0.007). WMH=white matter hyperintensities. Aβ₄₂=amyloid-β₄₂. B. Neurofilament Light & White Matter Hyperintensities by Amyloid Status Solid and dotted lines reflect unadjusted values of neurofilament light CSF biomarker concentrations (X axis) corresponding to WMH volume (Y axis) stratified by amyloid status for illustration purposes only. When covarying for age, sex, race/ethnicity, education, intracranial volume, cognitive diagnosis, and APOE4, neurofilament light related to WMH (β=0.0003, p=0.01) but did not interact with Aβ₄₂ on WMH (β<0.00001, p=0.36). WMH=white matter hyperintensities.

Figure 3. CSF Biomarker Concentrations of Amyloid-β₄₂ & Neurofilament Light in Association with White Matter Hyperintensities

A. Amyloid-β₄₂ & White Matter Hyperintensities Solid black line reflects unadjusted values of CSF Aβ₄₂ biomarker concentration (X axis) corresponding to WMH volume (Y axis) for illustration purposes only. When covarying for age, sex, race/ethnicity, education, intracranial volume, cognitive diagnosis, and APOE4, Aβ₄₂ related to WMH (β=−0.001, p=0.007). WMH=white matter hyperintensities. Aβ₄₂=amyloid-β₄₂. B. Neurofilament Light & White Matter Hyperintensities by Amyloid Status Solid and dotted lines reflect unadjusted values of neurofilament light CSF biomarker concentrations (X axis) corresponding to WMH volume (Y axis) stratified by amyloid status for illustration purposes only. When covarying for age, sex, race/ethnicity, education, intracranial volume, cognitive diagnosis, and APOE4, neurofilament light related to WMH (β=0.0003, p=0.01) but did not interact with Aβ₄₂ on WMH (β<0.00001, p=0.36). WMH=white matter hyperintensities.