Longitudinal Evidence for Dissociation of Anterior and Posterior MTL Resting-State Connectivity in Aging: Links to Perfusion and Memory

Abstract

Neuroimaging studies of spontaneous signal fluctuations as measured by resting-state functional magnetic resonance imaging have revealed age-related alterations in the functional architecture of brain networks. One such network is located in the medial temporal lobe (MTL), showing structural and functional variations along the anterior-posterior axis. Past cross-sectional studies of MTL functional connectivity (FC) have yielded discrepant findings, likely reflecting the fact that specific MTL subregions are differentially affected in aging. Here, using longitudinal resting-state data from 198 participants, we investigated 5-year changes in FC of the anterior and posterior MTL. We found an opposite pattern, such that the degree of FC within the anterior MTL declined after age 60, whereas elevated FC within the posterior MTL was observed along with attenuated posterior MTL-cortical connectivity. A significant negative change-change relation was observed between episodic-memory decline and elevated FC in the posterior MTL. Additional analyses revealed age-related cerebral blood flow (CBF) increases in posterior MTL at the follow-up session, along with a positive relation of elevated FC and CBF, suggesting that elevated FC is a metabolically demanding alteration. Collectively, our findings indicate that elevated FC in posterior MTL along with increased local perfusion is a sign of brain aging that underlie episodic-memory decline.

Keywords: episodic memory, functional connectivity, longitudinal, anterior and posterior MTL, perfusion.

Figure 1.

Two resting-state ICA components along the longitudinal hippocampal axis (2 different illustration methods). aMTL (red; left peak cluster XYZ: −28 −12 −20; right peak cluster XYZ: 28 −10 −22) and pMTL (green; left peak cluster XYZ: −18 −32 −14, left peak sub-cluster XYZ: −18 −26 −12; right peak cluster XYZ: 16 −30 −12, right peak sub-cluster XYZ: 18 −24 −10) RSNs (at the group level) are overlaid on the sample-specific template created using DARTEL. The white line represents Uncal apex landmark (Y = −21) which has been shown to be a reliable landmark for long-axis segmentation of the HC (Poppenk et al. 2013).

Figure 2.

Longitudinal changes of the aMTL and pMTL for 3 different ICA-driven measures (voxel-wise connectivity, global connectivity, and amplitude) after post-ICA motion correction. (A) Longitudinal changes in global FC (across the whole RSN shown in Fig. 1) of the aMTL (red) and the pMTL (green). An assumption-free general additive model (GAM) as a function of age was fitted to accurately describe changes across the adult lifespan. The shading represents ± 1 standard error. (B) Longitudinal increase in amplitude of the pMTL shown using GAM with a contour reflecting % 95 confidence band. (C) voxel-wise changes in FC of the aMTL and pMTL. The slice panel indicates brain regions exhibiting longitudinal decline (in red) and elevation (in green) for the aMTL and the pMTL, respectively. The unit for the global FC is percent signal changes (intensity normalization followed by no scaling; See method section).

Figure 3.

(A) Association between FC and CBF in pMTL (XYZ: 28 −32 −12; r = 0.23, P = 0.006). (B) Age-related increases in CBF of the pMTL (P = 7.6×10⁻⁵). A finite difference approximation of the first derivative along with 95% confidence limits confirmed a reliable increase in pMTL perfusion beginning at age 70 years.

Figure 4.

Changes in episodic memory in relation to changes in FC of the pMTL. (A) The slide panel indicates a brain regions (in yellow) of the whole pMTL (in red) in which longitudinal changes in FC are associated with changes in episodic memory. (B) Scatter plot displays change–change association between FC of the pMTL and episodic memory.