Reduced Frontal White Matter Hyperintensities in Superagers: Evidence of Resistance to Age-Related Structural Brain...

Superagers are older adults who maintain exceptional memory performance despite their age. This study aimed to investigate whether local differences in white matter hyperintensities (WMH) and microstructural integrity of normal-appearing white matter (NAWM) could help explain the superager phenotype.

This study included 31 cognitively normal older adults 80 years of age or older: Fourteen were classified as superagers; and 17, as cognitively average older adults. All participants underwent 3T MRI, including structural and diffusion-weighted imaging. WMH were automatically segmented using an adaptive Gaussian Mixture Model under multivariate data (T1WI, FLAIR), with their locations mapped to each participant's native brain anatomy. The white matter was divided by lobes and into 4 concentric equidistant radial layers (from periventricular to juxtacortical), visualized via a 2D "bulls eye" representation. WMH volumes were normalized to total intracranial volume. Diffusion preprocessing was performed using the FSL Diffusion Toolbox. For DTI analysis, fractional anisotropy (FA) and mean diffusivity (MD) were calculated from NAWM masks, defined by subtracting WMH lesion maps and applying a 1-voxel erosion to minimize partial volume effects. Statistical comparisons were conducted using the Mann-Whitney U test.

Superagers showed a trend (P = .19) toward lower median overall WMH burden (3.52 mL [interquartile range,: 2.13-8.45]) compared with controls (8.52 mL [interquartile range, 3.23-19.36]). In the frontal lobes, however, WMH load was notably lower in superagers, showing a trend toward significance (P = .09), with significant differences in the juxtacortical (P = .03, layers 3 + 4) and mid frontal (P = .04, layers 2 + 3) radial layers. DTI analysis revealed no significant group differences in the total and frontal NAWM integrity (P > .05), with similar median FA and MD values.

Using a novel regional mapping approach, we found that superagers exhibited a lower burden of frontal WMH, particularly in the juxtacortical and mid-white matter layers, which may contribute to their preserved cognitive performance. This is the first study to apply a detailed topographical analysis of WMH in superagers, reporting that reduced WMH in specific strategic brain areas could serve as a potential neuroimaging marker of the superager-resistant phenotype.