Trail Making Test B Shows the Strongest Structural Brain Associations in Healthy Aging

Cognitive tests are often used side by side in aging research, but a new neuroimaging analysis suggests they are not equivalent in how closely they track underlying brain structure. Using data from the Human Connectome Project–Aging, researchers report that commonly used measures—including the NIH Toolbox cognition composites and the Trail Making Tests—show distinct structural brain correlates, with the broadest associations observed for Trail Making Test Part B (TMT-B).

In the study, investigators examined associations between four cognitive measures—NIH Toolbox fluid cognition, crystallized cognition, TMT-A, and TMT-B—and multimodal MRI metrics in 725 healthy adults aged 36 to 100 years. Analyses adjusted for age, sex, and years of education. Diffusion MRI metrics (including fractional anisotropy, mean diffusivity, neurite density, orientation dispersion, and free water fraction) were available in a subset after preprocessing exclusions, and cortical thickness and volume were assessed using FreeSurfer-based morphometry.

Overall, better performance tended to align with patterns consistent with greater white matter microstructural integrity: higher crystallized and fluid cognition scores and faster TMT completion times were generally associated with higher FA and neurite density and lower mean diffusivity and free water fraction. However, the strength and extent of these relationships varied notably by test.

TMT-B showed the most widespread diffusion associations, involving major projection, commissural, and association pathways. Tracts highlighted in the results included regions of the corona radiata, corpus callosum, superior longitudinal fasciculus, and additional pathways such as parts of the internal capsule, external capsule, and middle cerebellar peduncle. Compared with the other measures, TMT-B’s diffusion signal covered a broader distribution of white matter systems.

Cortical morphometry findings followed a similar pattern. Worse TMT-B performance (longer completion time) was associated with smaller cortical volumes across multiple regions, including areas in the left precentral, supramarginal, paracentral, and superior parietal regions and the right lateral occipital, inferior temporal, transverse temporal, and postcentral regions. Thickness findings were mixed: worse TMT-B performance was associated with a thinner right superior temporal gyrus, while also showing an association with a thicker left fusiform gyrus.

TMT-A and crystallized cognition demonstrated intermediate, partially overlapping patterns. Both were associated with diffusion metrics in major tracts such as the corona radiata, corpus callosum, and superior longitudinal fasciculus, with TMT-A showing relationships across a higher number of diffusion metrics per tract than crystallized cognition in the paper’s tract summaries. In cortical analyses, crystallized cognition was associated with regional thickness and volume findings spanning sensorimotor, temporal, and parietal regions (including supramarginal and transverse temporal areas), while worse TMT-A performance was associated with smaller volumes in the left inferior parietal and right lateral occipital regions.

In contrast, fluid cognition showed comparatively limited structural correlates. In diffusion analyses, associations were most prominent in select projection and cerebellar-related pathways (and left superior longitudinal fasciculus in the tract summary), and cortical associations were restricted to a small number of regions in thickness and volume analyses.

The authors interpret these normative structure–cognition maps as a reference framework for selecting cognitive measures and for contextualizing MRI–cognition findings in aging research. They also note key limitations, including the study’s cross-sectional design and constrained adjustment for potential confounders based on available dataset variables.