Longitudinal Changes in Hippocampal Network Connectivity in Alzheimer's Disease

Abstract

Objective The hippocampus is connected to 2 distinct cortical brain networks, the posterior–medial and the anterior–temporal networks, involving different medial temporal lobe (MTL) subregions. The aim of this study was to assess the functional alterations of these 2 networks, their changes over time, and links to cognition in Alzheimer's disease. Methods We assessed MTL connectivity in 53 amyloid‐β–positive patients with mild cognitive impairment and AD dementia and 68 healthy elderly controls, using resting‐state functional magnetic resonance imaging, cross‐sectionally and longitudinally. First, we compared the functional connectivity of the posterior–medial and anterior–temporal networks within the control group to highlight their specificities. Second, we compared the connectivity of these networks between groups, and between baseline and 18‐month follow‐up in patients. Third, we assessed the association in the connectivity changes between the 2 networks, and with cognitive performance. Results We found decreased connectivity in patients specifically between the hippocampus and the posterior–medial network, together with increased connectivity between several MTL subregions and the anterior–temporal network. Moreover, changes in the posterior–medial and anterior–temporal networks were interrelated such that decreased MTL–posterior–medial connectivity was associated with increased MTL–anterior–temporal connectivity. Finally, both MTL–posterior–medial decrease and MTL–anterior–temporal increase predicted cognitive decline. Interpretation Our findings demonstrate that longitudinal connectivity changes in the posterior–medial and anterior–temporal hippocampal networks are linked together and that they both contribute to cognitive decline in Alzheimer's disease. These results shed light on the critical role of the posterior–medial and anterior–temporal networks in Alzheimer's disease pathophysiology and clinical symptoms. ANN NEUROL 2021;90:391–406

Functional Redundancy of the Posterior Hippocampi, but not Anterior Hippocampi or Left Frontal Cortex, is Disrupted in Pathological Brain Aging

“…In regard to the anterior HC, we observed that redundancy levels were not affected by A β -status. This finding is in-line with the reported distinct vulnerability of anterior and posterior hippocampal systems to AD pathology (Dautricourt et al, 2021; Maass et al, 2019), such that the posterior networks are selectively targeted by A β pathology while anterior networks are vulnerable to tau pathology (Adams, Maass, Harrison, Baker, & Jagust, 2019; Maass et al, 2019). Though there were no amyloid effects on anterior HC redundancy, we did find evidence of diagnostic differences, particularly when the global redundancy measure was segregated into direct and indirect components.…”

“…On the other hand, the posterior HC is strongly connected to PM regions, including the posteriomedial entorhinal cortex, parahippocampal cortex, retrosplenial cortex, posterior cingulate cortex (PCC), and precuneus and underscores processing contextual information of episodic memory (Kahn et al, 2008; Libby et al, 2012; Ranganath & Ritchey, 2012). The AT and PM systems are further differentiated by their selective susceptibility to AD pathology, as regions of the AT network are most burdened by tau pathology while the PM network is most vulnerable to A β pathology (Dautricourt et al, 2021; Maass et al, 2019). The susceptibility of the PM system to A β pathology is supported by the extant AD literature, which demonstrates that major hubs of the PM, including the precuneus and posterior cingulate cortex, that show a high degree of connectivity throughout the brain (van den Heuvel & Sporns, 2013), are some of the earliest regions to exhibit and drive A β pathology deposition (Buckner, Andrews-Hanna, & Schacter, 2008; Palmqvist et al, 2017; Pasquini et al, 2017).…”

Entorhinal-hippocampal circuit integrity is related to mnemonic discrimination and amyloid-β pathology in older adults

“…Because increased FC was associated with Aβ pathology and neurodegeneration, it suggests that hyperconnectivity is dysfunctional rather than compensatory. A pathological increase in FC between the entorhinal cortex and hippocampus at rest is supported by previous findings 38, 40, 46, 47 . For example, studies comparing resting state FC between patients with MCI or AD with elderly controls have found increased FC between entorhinal cortex and the hippocampus, particularly with the hippocampal head 38 , consistent with our results.…”

A Spatiotemporal Brain Network Analysis of Alzheimer’s Disease Based on Persistent Homology

“…Then, current research is limited to the analysis of the rs-fMRI data collected in a single time period and does not verify multiple time periods. In the future, we will study the longitudinal trajectories ( Dautricourt et al, 2021 ) of functional brain dynamics over multiple time periods. Last but not least, although this article interprets the temporal dynamics of the functional brain network well and has obtained good experimental results, a correlation analysis with behavioral data should be performed in the future.…”