Age-related differences in regional brain volumes: a comparison of optimized voxel-based morphometry to manual volumetry

Abstract

Regional manual volumetry is the gold standard of in vivo neuroanatomy, but is labor-intensive, can be imperfectly reliable, and allows for measuring limited number of regions. Voxel-based morphometry (VBM) has perfect repeatability and assesses local structure across the whole brain. However, its anatomic validity is unclear, and with its increasing popularity, a systematic comparison of VBM to manual volumetry is necessary. The few existing comparison studies are limited by small samples, qualitative comparisons, and limited selection and modest reliability of manual measures. Our goal was to overcome those limitations by quantitatively comparing optimized VBM findings with highly reliable multiple regional measures in a large sample (N=200) across a wide agespan (18-81). We report a complex pattern of similarities and differences. Peak values of VBM volume estimates (modulated density) produced stronger age differences and a different spatial distribution from manual measures. However, when we aggregated VBM-derived information across voxels contained in specific anatomically defined regions (masks), the patterns of age differences became more similar, although important discrepancies emerged. Notably, VBM revealed stronger age differences in the regions bordering CSF and white matter areas prone to leukoaraiosis, and VBM was more likely to report nonlinearities in age-volume relationships. In the white matter regions, manual measures showed stronger negative associations with age than the corresponding VBM-based masks. We conclude that VBM provides realistic estimates of age differences in the regional gray matter only when applied to anatomically defined regions, but overestimates effects when individual peaks are interpreted. It may be beneficial to use VBM as a first-pass strategy, followed by manual measurement of anatomically defined regions.

Figure 1

Examples of MRI images prepared for manual (A) and VBM (B) processing. Manual alignment involving rotation of the brain volume to correct for head tilt, pitch, and rotation was performed on each subject’s high-resolution scan (A). For VBM (B), segmentation map produced after skull stripping, stretching to standard space, and smoothing. Note the observable difference in the resulting image resolution quality between the two methods.

Figure 2

Examples of manually traced Regions of Interest (ROI): (a) dorsolateral prefrontal cortex (left), orbito-frontal cortex (right), and anterior cingulate gyrus (middle); (b) hippocampus; (c) clockwise: parahippocampal gyrus (P), fusiform (F) and inferior temporal (I) cortices; (d) pre-central gyrus: cortex (left), pre-central white matter (right); (e) post-central gyrus: cortex (left), post-central white matter (right); (f) inferior parietal lobule; cortex (right), white matter (left); (g) visual (calcarine) cortex.

Figure 3

Example of manually drawn ROI masks for VBM analysis. The same ROIs were manually drawn on a representative subject in native space and then registered to standard space to create the masks for a quantitative comparison of VBM and manual volumetry.

Figure 4

VBM Gray Matter Results: Statistical parametric maps for age differences in gray matter revealed significant age-related reduction in modulated density in all lobes. The strongest effects were limited to the regions of parenchyma-CSF interface such as Sylvian and interhemispheric fissures, especially the superior temporal gyrus. The SPM is a map of significant Z-statistic values that correspond in color to the magnitude legend to the right, with the yellow voxels having an effect of up to 10.5. Note that because these are Z values, they can be directly compared to the magnitude of effects for white matter in Figure 5.

Figure 5

VBM White Matter Results: Statistical parametric maps for age differences in white matter revealed age-related differences in modulated density were considerably less widespread than in gray matter and concentrated in the anterior and middle corpus callosum, periventricular areas and cerebellar peduncles. Note that the largest effects for white matter were in the yellow voxels, with values of up to 7.15, substantially smaller than the gray matter effects (of up to 10.5) shown in Figure 4.

Figure 6

Scatterplots of bivariate relations between age manual volumes or VBM-derived partial volume estimates for prefrontal gray matter regions (dorsolateral prefrontal cortex, orbitofrontal cortex, anterior cingulate gyrus). All regressions were conducted using intracranial volume adjustment.

Figure 7

Scatterplots of bivariate relations between age manual volumes or VBM-derived partial volume estimates for temporal lobe gray matter regions (hippocampus, parahippocampal gyrus, fusiform gyrus, inferior temporal gyrus). All regressions were conducted using intracranial volume adjustment.

Figure 8

Scatterplots of bivariate relations between age manual volumes or VBM-derived partial volume estimates for primary motor and somatosensory cortices (gray and white matter). All regressions were conducted using intracranial volume adjustment.

Figure 9

Scatterplots of bivariate relations between age manual volumes or VBM-derived partial volume estimates for prefrontal cortex white matter, inferior parietal lobule (gray and white matter), primary visual (calcarine) cortex. All regressions were conducted using intracranial volume adjustment.