Age-related regional network of magnetic resonance imaging gray matter in the rhesus macaque

Abstract

Human structural neuroimaging studies have supported the preferential effects of healthy aging on frontal cortex, but reductions in other brain regions have also been observed. We investigated the regional network pattern of gray matter using magnetic resonance imaging (MRI) in young adult and old rhesus macaques (RMs) to evaluate age effects throughout the brain in a nonhuman primate model of healthy aging in which the full complement of Alzheimer's disease (AD) pathology does not occur. Volumetric T1 MRI scans were spatially normalized and segmented for gray matter using statistical parametric mapping (SPM2) voxel-based morphometry. Multivariate network analysis using the scaled subprofile model identified a linear combination of two gray matter patterns that distinguished the young from old RMs. The combined pattern included reductions in bilateral dorsolateral and ventrolateral prefrontal and orbitofrontal and superior temporal sulcal regions with areas of relative preservation in vicinities of the cerebellum, globus pallidus, visual cortex, and parietal cortex in old compared with young RMs. Higher expression of this age-related gray matter pattern was associated with poorer performance in working memory. In the RM model of healthy aging, the major regionally distributed effects of advanced age on the brain involve reductions in prefrontal regions and in the vicinity of the superior temporal sulcus. The age-related differences in gray matter reflect the effects of healthy aging that cannot be attributed to AD pathology, providing support for the targeted effects of aging on the integrity of frontal lobe regions and selective temporal lobe areas and their associated cognitive functions.

Figure 1.

MRI template for the rhesus macaque. A customized MRI template was created for the sample of 19 MRI scans using SPM2 voxel-based morphometry and an iterative procedure using sample-specific segmentation priors adapted for the rhesus macaque. The average whole-brain template is shown in sagittal, coronal, and axial views.

Figure 2.

Behavioral performance comparing the young (n = 5) and elderly (n = 11) adult rhesus monkey groups on DR and DNMS tasks. Left, The comparison between age groups for the DR task with multiple retention intervals. Right, The age-group comparisons for the DNMS task for increasing retention intervals. The y-axes for both graphs show the percentage correct performance, whereas the retention intervals administered for each task are shown on the x-axes. Average performance with error bars indicating SEM is shown for each retention interval. Significant group differences using the nonparametric Mann–Whitney U test are indicated by *p ≤ 0.05, **p ≤ 0.02, and ***p ≤ 0.002.

Figure 3.

Multiple regression of SSM subject scores from the network analysis of MRI voxel-based morphometry in young adult (n = 7) and elderly (n = 12) rhesus macaques. The scatterplot shows that the aged monkey group has a higher expression of the MRI age-related network pattern than does the young monkey group. The age-related network subject scores were derived from the linear combination of the second and third SSM component patterns.

Figure 4.

MRI gray matter pattern reflecting the linear combination of two SSM components whose subject scores predicted age group in the rhesus macaques. Voxels with SSM pattern weights are superimposed on axial slices from the SPM2 customized template for the rhesus macaque. The blue end of the color scale indicates brain regions showing lower gray matter volume with older age, whereas the orange end of the scale shows areas of relative increased gray matter with increasing age. Thus, a subject with a high positive score for this age-related pattern has relatively greater reductions in the blue areas and relatively greater covarying increases in the orange areas. Only voxels with z scores ≥|2.5| after bootstrap resampling to provide robust regional pattern weights are shown. Notable regions of reduction (blue) with older age are observed (from top to bottom rows), mainly in the vicinities of the bilateral superior temporal sulcus, lateral fissure, and ventrolateral and dorsolateral prefrontal regions, whereas relative increases (orange) are seen in the vicinities of left cerebellum, left visual cortex, bilateral globus pallidus, and a left parietal region. That the older monkeys had a higher mean network age pattern score, with most of them having scores that were higher than the young and in the positive range, is consistent with a higher expression of the hypothesized age-related regional pattern in that group, including greater reductions in the blue areas than in the young. L, Left; R, right.

Figure 5.

Regression analyses showing the association between behavioral performance on a DR task summary score with the subject scores from the age-related network SSM pattern. The old rhesus macaques are shown by filled circles and the young macaques have open circles in the scatterplot. A higher expression of the network age pattern is associated with poorer task performance for both the young and old groups combined (r = −0.64, p ≤ 0.008, n = 16), as well as for the old macaque group alone (r = −0.63, p ≤ 0.038, n = 11).