Dedifferentiation of caudate functional connectivity and striatal dopamine transporter density predict memory change in normal aging

Abstract

Age-related changes in striatal function are potentially important for predicting declining memory performance over the adult life span. Here, we used fMRI to measure functional connectivity of caudate subfields with large-scale association networks and positron emission tomography to measure striatal dopamine transporter (DAT) density in 51 older adults (age 65-86 years) who received annual cognitive testing for up to 7 years (mean = 5.59, range 2-7 years). Analyses showed that cortical-caudate functional connectivity was less differentiated in older compared with younger adults (n = 63, age 18-32 years). Unlike in younger adults, the central lateral caudate was less strongly coupled with the frontal parietal control network in older adults. Older adults also showed less "decoupling" of the caudate from other networks, including areas of the default network (DN) and the hippocampal complex. Contrary to expectations, less decoupling between caudate and the DN was not associated with an age-related reduction of striatal DAT, suggesting that neurobiological changes in the cortex may drive dedifferentiation of cortical-caudate connectivity. Reduction of specificity in functional coupling between caudate and regions of the DN predicted memory decline over subsequent years at older ages. The age-related reduction in striatal DAT density also predicted memory decline, suggesting that a relation between striatal functions and memory decline in aging is multifaceted. Collectively, the study provides evidence highlighting the association of age-related differences in striatal function to memory decline in normal aging.

Keywords: aging; dopamine; functional connectivity; memory; striatum.

Fig. 1.

Factor scores for memory for 51 individuals from the main study sample of older adults. Black lines connect different measurements in the same individual. The red line indicates mean change, estimated using a GAMM.

Fig. 2.

Dedifferentiation of caudate FPN connectivity in older adults. (A) Voxelwise parcellation of the caudate (highlighted, Top) in young (Middle) and the main study sample of older adults (Bottom). Orange voxels are allocated to the FPN and red voxels to the DN. Voxels of other colors are allocated to other cortical networks and are not discussed further because of their small extent and location at the borders with cerebrospinal fluid. (B) Mean connectivity strength (z) between caudate FPN ROI and cortical ROIs in the FPN and the DN. The pattern for older adults is less differentiated than that for younger adults (significant age × ROI interactions, P < 0.05).

Fig. 3.

Whole-brain fc of a bilateral caudate FPN seed [Montreal Neurological Institute (MNI): x = −12, y = 10, z = 8; x = 12, y = 10, z = 8]. (A) Older > young adults = red-yellow; older < young adults = blue. ACC, anterior cingulate cortex; ITG, inferior temporal gyrus; MT+, middle temporal area; PCa, anterior inferior parietal cortex; PCC, posterior cingulate cortex; PCp, posterior inferior parietal cortex; PFCl, lateral prefrontal cortex; PFCm, medial prefrontal cortex; PHC, parahippocampal sulcus; STS, superior temporal sulcus. (B and C) Mean connectivity map for older (B) and younger (C) adults. Red-yellow regions are positively connected with the seed, blue regions negatively. (D) Age group differences in subcortical connectivity with the caudate FPN seed. Older > young adults = red-yellow; older < young adults = blue. For illustration, mean functional connectivity estimates are shown thresholded at T > 2.4 (P < 0.01). Bar graph illustrates mean connectivity of the caudate FPN seed with the hippocampus (HC) and midbrain (SN/VTA) by age group (older adults = gray bars; younger adults = black bars).

Fig. 4.

Predictors of memory change. Memory decline is pronounced in individuals over age 75 y with low decoupling between the caudate FPN subfield and the cortical DN (A) and low striatal DAT (B). For all groups, lines are the estimated mean slopes for memory change from a linear mixed-effects model with random intercept and fixed slope. Intercepts are adjusted to zero for illustration. Points are the corresponding observed mean values for memory (with SE) at each time point. <75 = older adults under age 75, >75 = older adults 75+ y.