Aging and Alzheimer's disease have dissociable effects on local and regional medial temporal lobe connectivity

Abstract

Functional disruption of the medial temporal lobe-dependent networks is thought to underlie episodic memory deficits in aging and Alzheimer's disease. Previous studies revealed that the anterior medial temporal lobe is more vulnerable to pathological and neurodegenerative processes in Alzheimer's disease. In contrast, cognitive and structural imaging literature indicates posterior, as opposed to anterior, medial temporal lobe vulnerability in normal aging. However, the extent to which Alzheimer's and aging-related pathological processes relate to functional disruption of the medial temporal lobe-dependent brain networks is poorly understood. To address this knowledge gap, we examined functional connectivity alterations in the medial temporal lobe and its immediate functional neighbourhood-the Anterior-Temporal and Posterior-Medial brain networks-in normal agers, individuals with preclinical Alzheimer's disease and patients with Mild Cognitive Impairment or mild dementia due to Alzheimer's disease. In the Anterior-Temporal network and in the perirhinal cortex, in particular, we observed an inverted 'U-shaped' relationship between functional connectivity and Alzheimer's stage. According to our results, the preclinical phase of Alzheimer's disease is characterized by increased functional connectivity between the perirhinal cortex and other regions of the medial temporal lobe, as well as between the anterior medial temporal lobe and its one-hop neighbours in the Anterior-Temporal system. This effect is no longer present in symptomatic Alzheimer's disease. Instead, patients with symptomatic Alzheimer's disease displayed reduced hippocampal connectivity within the medial temporal lobe as well as hypoconnectivity within the Posterior-Medial system. For normal aging, our results led to three main conclusions: (i) intra-network connectivity of both the Anterior-Temporal and Posterior-Medial networks declines with age; (ii) the anterior and posterior segments of the medial temporal lobe become increasingly decoupled from each other with advancing age; and (iii) the posterior subregions of the medial temporal lobe, especially the parahippocampal cortex, are more vulnerable to age-associated loss of function than their anterior counterparts. Together, the current results highlight evolving medial temporal lobe dysfunction in Alzheimer's disease and indicate different neurobiological mechanisms of the medial temporal lobe network disruption in aging versus Alzheimer's disease.

Keywords: AT network; Alzheimer’s disease; PM network; aging; medial temporal lobe connectivity.

Graphical abstract

Figure 1

MTL subregions and their functional interactions with each other. (A) Example ASHS-T1 segmentation from a single participant; (B) Intra-MTL connectome in normal agers (N = 116). One-sided one-sample t-tests with the FDR correction for multiple comparisons were used to test for the presence of positive functional coupling. The connectogram on the left is based on standard correlational connectivity. The connectogram on the right is based on partial correlations and represents direct connectivity within the MTL. Edge thickness in both connectograms is proportional to the t-static score of each connection. Abbreviations: PRC = perirhinal cortex; ERC = entorhinal cortex; PHC = parahippocampal cortex; aHP = anterior hippocampus; pHP = posterior hippocampus; MTL = medial temporal lobe; FDR = false discovery rate; ROI = region of interest.

Figure 2

The extended MTL network. Cortical regions with positive functional connectivity to the anterior or posterior tau-based MTL ROIs were identified and mapped onto ROI-based representation. The resulting set of 225 ROIs was termed the Extended MTL Network. The Extended MTL Network was identified using the normal agers group (N = 116). Abbreviations: MTL = medial temporal lobe; TFCE = threshold-free cluster enhancement; FDR = false discovery rate; ROI = region of interest.

Figure 3

AT and PM network estimation. Direct functional connections within the Extended MTL Network (see Fig. 2) from the normal agers group (N = 116) were identified using the graphical SCAD estimation method with BIC-based model selection. Network communities within the Extended MTL Network were identified using consensus Louvain modularity. Abbreviations: AT = anterior-temporal; PM = posterior-medial; MTL = medial temporal lobe; Ant. = anterior; Post. = posterior; Dors. = dorsal; SCAD = smoothly clipped absolute deviation estimator; ROI = region of interest.

Figure 4

AT and PM network architecture. The top panel depicts direct intra-AT and intra-PM functional connections in the normal agers group (N = 116). The bottom panel depicts direct AT-PM inter-network connections in the normal agers group (N = 116). The AT-affiliated ROIs and intra-AT connections are in purple; the PM-affiliated ROIs and intra-PM connections are in green. The AT-PM inter-network connections are in grey/black. The anterior and posterior tau-based MTL ROIs are marked with a yellow asterisk. Abbreviations: AT = anterior-temporal; PM = posterior-medial; MTL = medial temporal lobe.

Figure 5

The effects of (A) age and (B-E) Alzheimer’s disease progression on intra-MTL functional connectivity. The NBS-based GLM approach was used to assess the statistical significance of each contrast/comparison (N_{Aβ− CU} = 80, N_{Aβ+ CU} = 23, N_{Aβ+ CI} = 40). (B) Matrix-form representation of connectivity differences between Aβ-positive individuals with preclinical Alzheimer’s disease and Aβ-negative age-matched controls (univariate GLMs at the connection level; N_contrast = 103). (E) Left panel: intra-MTL connection cluster with an inverted ‘U-shaped’ functional connectivity pattern in Alzheimer’s disease (GLM-based quadratic trend analysis; N_contrast = 143). Right panel: violin plot depicting this cluster’s mean functional connectivity scores in controls, individuals with preclinical Alzheimer’s disease, and patients with symptomatic Alzheimer’s disease. Data points represent connectivity scores from individual participants. Abbreviations: PRC = perirhinal cortex; ERC = entorhinal cortex; PHC = parahippocampal cortex; aHP = anterior hippocampus; pHP = posterior hippocampus; CU = cognitively unimpaired; CI = cognitively impaired; Aβ− = amyloid-negative; Aβ+ = amyloid-positive; GLM = general linear model; NBS = network-based statistic(s).

Figure 6

Effects of (A) age and (B-D) Alzheimer’s disease progression on intra-network connectivity of the AT and PM systems. In each comparison, NBS-based GLMs were used to test for the presence of statistical group differences (N_{Aβ− CU} = 80, N_{Aβ+ CU} = 23, N_{Aβ+ CI} = 40). AT nodes and P-values are in purple; PM nodes and P-values are in green. Tau-based MTL ROIs are marked with a yellow asterisk. Abbreviations: AT = anterior-temporal network; PM = posterior-medial network; MTL = medial temporal lobe; CU = cognitively unimpaired; CI = cognitively impaired; Aβ− = amyloid-negative; Aβ+ = amyloid-positive; GLM = general linear model; NBS = network-based statistic(s); ROI = region of interest.

Figure 7

Age relationships for aMTL_tau-AT and pMTL_tau-PM functional connectivity. The aMTL_tau-AT/pMTL_tau-PM connectivity metric was computed by averaging connectivity values of those edges that represented direct functional interactions between the aMTL_tau (or pMTL_tau) ROIs and their one-hop neighbours in the AT (or PM) network (top and bottom glass brains, respectively). Lifespan trajectories for normal agers were fitted using multiple regression (N = 116). Thin lines around fitted age trajectories represent 95% confidence intervals. The AT network’s nodes and edges are shown in purple; those of the PM network are shown in green. Tau-based MTL ROIs are marked with a yellow asterisk. Abbreviations: AT = anterior-temporal; PM = posterior-medial; MTL = medial temporal lobe; aMTL_tau = tau-based anterior MTL ROI; pMTL_tau = tau-based posterior MTL ROI; CU Aβ− = cognitively unimpaired amyloid-negative; Ant. = anterior; Post. = posterior; ROI = region of interest.

Figure 8

Effect of Alzheimer’s disease progression on aMTL_tau-AT and pMTL_tau-PM functional connectivity. The violin plot in the centre depicts mean aMTL_tau-AT and pMTL_tau-PM connectivity scores in Aβ-negative CU older adults (N_{Aβ− CU} = 80), Aβ-positive CU individuals with preclinical Alzheimer’s disease (N_{Aβ+ CU} = 23), and Aβ-positive individuals with symptomatic Alzheimer’s disease (N_{Aβ+ CI} = 40). Data points represent connectivity scores from individual participants. GLMs were used to test for the presence of connectivity differences between the three groups. Statistically significant Holm-Bonferroni-corrected pairwise comparisons are highlighted. The aMTL_tau-AT/pMTL_tau-PM connections from which overall aMTL_tau-AT/pMTL_tau-PM connectivity values were computed are shown to the left/right of the violin plot. Tau-based MTL ROIs are marked with a yellow asterisk. Abbreviations: AT = anterior-temporal; PM = posterior-medial; MTL = medial temporal lobe; aMTL_tau = tau-based anterior MTL ROI; pMTL_tau = tau-based posterior MTL ROI; CU = cognitively unimpaired; CI = cognitively impaired; Aβ− = amyloid-negative; Aβ+ = amyloid-positive; GLM = general linear model; ROI = region of interest.