Abstract
Purpose: To assess age-related changes in intrinsic functional brain connectivity and hemodynamics during adulthood in the context of the retrogenesis hypothesis, which states that the rate of age-related changes is higher in late-myelinating (prefrontal, lateral-posterior temporal) cerebrocortical areas as compared to early myelinating (parietal, occipital) regions. In addition, to examine the dependence of age-related changes upon concurrent subclinical depression symptoms which are common even in healthy aging.Methods: Sixty-four healthy adults (28 men) aged 23–79 years (mean 45.0, SD = 18.8 years) were examined. Resting-state functional MRI (rs-fMRI) time series were used to compute voxel-wise intrinsic connectivity contrast (ICC) maps reflecting the strength of functional connectivity between each voxel and the rest of the brain. We further used Time Shift Analysis (TSA) to estimate voxel-wise hemodynamic lead or lag for each of 22 ROIs from the automated anatomical atlas (AAL).Results: Adjusted for depression symptoms, gender and education level, reduced ICC with age was found primarily in frontal, temporal regions, and putamen, whereas the opposite trend was noted in inferior occipital cortices (p < 0.002). With the same covariates, increased hemodynamic lead with advancing age was found in superior frontal cortex and thalamus, with the opposite trend in inferior occipital cortex (p < 0.002). There was also evidence of reduced coupling between voxel-wise intrinsic connectivity and hemodynamics in the inferior parietal cortex.Conclusion: Age-related intrinsic connectivity reductions and hemodynamic changes were demonstrated in several regions—most of them part of DMN and salience networks—while impaired neurovascular coupling was, also, found in parietal regions. Age-related reductions in intrinsic connectivity were greater in anterior as compared to posterior cortices, in line with implications derived from the retrogenesis hypothesis. These effects were affected by self-reported depression symptoms, which also increased with age.
Highlights
We examined changes in hemodynamic response and associated intrinsic connectivity associated with healthy aging, by assessing voxel-level hemodynamic and functional connectivity indices derived from a single technique, using time-shift analysis
Significant effects of age indicating lower Intrinsic Connectivity Contrast (ICC) in older as compared to younger participants were found in IFG: F(1,62) = 10.28, p = 0.002, vmPFC: F(1,62) = 7.44, p = 0.01, dlPFC: F(1,62) = 7.05, p = 0.01, SMA: F(1,62) = 16.04, p < 0.001, posterior cingulate cortex (PCC): F(1,62) = 10.04, p = 0.002, temporal pole: F(1,62) = 12.17, p = 0.001, insula: F(1,62) = 8.49, p = 0.005, and putamen: F(1,62) = 13.08, p = 0.001
In models that included gender, education, and depression symptoms as covariates, the effect of age was reduced in the majority of ROIs and remained significant in the temporal pole [F(1,61) = 4.20, p = 0.05; Partialrage−ICC = 0.435, p = 0.001], vmPFC [F(1,61) = 6.92, p = 0.01; Partialrage−ICC = 0.426, p = 0.002], putamen [F(1,61) = 3.99, p = 0.05; Partialrage−ICC = 0.384, p = 0.005], and inferior occipital gyrus [F(1,61) = 4.08, p = 0.05; Partialrage−ICC =-0.360, p = 0.009; see Figure 2]
Summary
The majority of imaging studies on the effect of healthy aging on cerebral hemodynamics have examined cross-sectional changes in brain metabolism using SPECT [1, 2] or FDG-PET [3,4,5,6,7,8,9,10,11] and cortical perfusion using Arterial Spin Labeling (ASL) [12,13,14,15,16,17,18,19,20,21]. With certain exceptions [6, 7], the majority of studies reported decreased cerebral metabolism with age which tends to be more pronounced in the frontal lobe, especially in rostral and ventral prefrontal regions, the temporal pole, and caudate [8,9,10,11]. Age-related regional CBF reductions were, found by ASL, predominantly in frontal lobes [12, 13, 19]. The areas noted for age-related reductions in CBF were virtually identical to those found by Chen et al [15]
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