Age-Related Decline in Brain Myelination: Quantitative Macromolecular Proton Fraction Mapping, T2-FLAIR Hyperintensity Volume, and Anti-Myelin Antibodies Seven Years Apart

Abstract

Age-related myelination decrease is considered one of the likely mechanisms of cognitive decline. The present preliminary study is based on the longitudinal assessment of global and regional myelination of the normal adult human brain using fast macromolecular fraction (MPF) mapping. Additional markers were age-related changes in white matter (WM) hyperintensities on FLAIR-MRI and the levels of anti-myelin autoantibodies in serum. Eleven healthy subjects (33-60 years in the first study) were scanned twice, seven years apart. An age-related decrease in MPF was found in global WM, grey matter (GM), and mixed WM-GM, as well as in 48 out of 82 examined WM and GM regions. The greatest decrease in MPF was observed for the frontal WM (2-5%), genu of the corpus callosum (CC) (4.0%), and caudate nucleus (5.9%). The age-related decrease in MPF significantly correlated with an increase in the level of antibodies against myelin basic protein (MBP) in serum (r = 0.69 and r = 0.63 for global WM and mixed WM-GM, correspondingly). The volume of FLAIR hyperintensities increased with age but did not correlate with MPF changes and the levels of anti-myelin antibodies. MPF mapping showed high sensitivity to age-related changes in brain myelination, providing the feasibility of this method in clinics.

Keywords: FLAIR hyperintensities; MPF; demyelination; macromolecular fraction mapping; myelin; myelin-specific autoantibodies; neuroimaging; normal aging; quantitative MRI; white matter.

Figure 1

An example of T1 Eve template [62] registration with segmentation (a) to individual MPF map (b). Slices are shown in similar axial, sagittal, and coronal projections. R-L—right to left, S-I—superior to inferior.

Figure 2

Age-related global changes of brain myelination for WM, GM, and mixed WM–GM compartments. (a) Example MPF map and corresponding masks of cerebrospinal fluid (CSF), GM, WM, and mixed WM–GM used for global measurements. (b) Absolute MPF decrease in global GM, WM, and mixed WM–GM. (c) Percentage MPF decrease in global GM, WM, and mixed WM–GM. (d) Volume changes in GM, WM, and mixed WM–GM. Error bars denote standard deviation. Significant differences: *—p < 0.05, **—p < 0.01, ***—p < 0.001.

Figure 3

Age-related changes between MPF measurements obtained in 2015 and 2022 for the separate brain regions: (a) juxtacortical WM of left and right hemispheres, (b) allocortex, subcortical GM, and brainstem, and (c) WM pathways. (d)—Example segmentation on an individual MPF map (upper row) and 3D reconstruction of three sets of brain structures corresponding to (a–c) measurements. Colors correspond to the labels of separate brain structures. Significant differences between 2015 and 2022: *—p < 0.05, **—p < 0.01. ***—p < 0.001. Significant differences between left and right hemispheres: +—p < 0.05, ++—p < 0.01. +++—p < 0.001. The significance of the differences is marked on the side of the hemisphere in which the MPF is larger. Error bars correspond to SD.

Figure 4

Age-related percentage changes between average MPF measurements obtained in 2015 and 2022 for the separate brain regions: (a) juxtacortical WM of left and right hemispheres, (b) WM pathways, (c) allocortex, subcortical GM, and brainstem. Significant differences between 2015 and 2022: *—p < 0.05, **—p < 0.01. ***—p < 0.001.

Figure 5

Regions of a significant age-related decrease in MPF in representative cross-sections of a 3D MPF map at different levels of axial (a) and coronal (b) projections of an individual MPF map. Regions of significant MPF decrease are marked by red color.

Figure 6

Age-related changes in the volume of T2-FLAIR hyperintensities and MPF in hyperintense zones. (a)—Example T2-FLAIR images and MPF maps obtained from the same subject in 2015 and 2022. T2-FLAIR hyperintensities correspond to MPF hypointensities are marked by red arrows. (b)—Quantitative differences in the volume of T2-FLAIR hyperintensities and MPF in it. Significant differences: *—p < 0.05. Error bars correspond to SD.