Aberrant functional connectivity differentiates retrosplenial cortex from posterior cingulate cortex in prodromal Alzheimer's disease

The cholinergic basal forebrain (CBF), comprising different groups of cortically projecting cholinergic neurons, plays a crucial role in higher cognitive processes and has been implicated in diverse neuropsychiatric disorders. A distinct corticotopic organization of CBF projections has been revealed in animal studies, but little is known about their organization in the human brain. We explored regional differences in functional connectivity (FC) profiles within the human CBF by applying a clustering approach to resting‐state functional magnetic resonance imaging (rs‐fMRI) data of healthy adult individuals (N = 85; 19–85 years). We further examined effects of age on FC of the identified CBF clusters and assessed the reproducibility of cluster‐specific FC profiles in independent data from healthy older individuals (N = 25; 65–89 years). Results showed that the human CBF is functionally organized into distinct anterior‐medial and posterior‐lateral subdivisions that largely follow anatomically defined boundaries of the medial septum/diagonal band and nucleus basalis Meynert. The anterior‐medial CBF subdivision was characterized by connectivity with the hippocampus and interconnected nodes of an extended medial cortical memory network, whereas the posterior‐lateral subdivision was specifically connected to anterior insula and dorsal anterior cingulate components of a salience/attention network. FC of both CBF subdivisions declined with increasing age, but the overall topography of subregion‐specific FC profiles was reproduced in independent rs‐fMRI data of healthy older individuals acquired in a typical clinical setting. Rs‐fMRI‐based assessments of subregion‐specific CBF function may complement established volumetric approaches for the in vivo study of CBF involvement in neuropsychiatric disorders.

Section: Discussionsupporting

confidence: 76%

The corticotopic organization of the human basal forebrain as revealed by regionally selective functional connectivity profiles

Fritz

Ray

Dyrba

et al. 2018

“…However, ventral PCC exhibited dense local FC primarily restricted to the DMN (Leech & Sharp, ; Leech et al, ; Spreng et al, ; Tomasi & Volkow, ). Although RSC may partly overlap with ventral PCC, as reported in some previous studies (Dastjerdi et al, ; Dillen et al, ; Leech & Sharp, ; Vann et al, ), its centrality has never been directly compared to the other cortical areas of DMN. Given previous evidence in support of age‐related functional dissociation between PCC and RSC (Mevel et al, ), it is indeed important to investigate the centrality roles of PCC and RSC in older age separately.…”

Section: Introductionmentioning

confidence: 93%

“…The heterogeneity within the posterior DMN might also contribute to discrepant findings. Human and animal studies indicate that the medial parietal cortex, including PCC and RSC, is a heterogeneous region, and that it is important to distinguish RSC from PCC due to morphological and connectivity differences (Aggleton, ; Dastjerdi et al, ; Dillen et al, ; Kobayashi & Amaral, ; Leech et al, ; Mufson & Pandya, ; Vann et al, ). Critically, the density of HC‐RSC connections was found to be much higher than the density of HC connections to adjacent PCC areas (Kobayashi & Amaral, ; Mufson & Pandya, ).…”

Section: Introductionmentioning

confidence: 99%

The retrosplenial cortex: A memory gateway between the cortical default mode network and the medial temporal lobe

Kaboodvand

Bäckman

Nyberg

et al. 2018

The default mode network (DMN) involves interacting cortical areas, including the posterior cingulate cortex (PCC) and the retrosplenial cortex (RSC), and subcortical areas, including the medial temporal lobe (MTL). The degree of functional connectivity (FC) within the DMN, particularly between MTL and medial-parietal subsystems, relates to episodic memory (EM) processes. However, past resting-state studies investigating the link between posterior DMN-MTL FC and EM performance yielded inconsistent results, possibly reflecting heterogeneity in the degree of connectivity between MTL and specific cortical DMN regions. Animal work suggests that RSC has structural connections to both cortical DMN regions and MTL, and may thus serve as an intermediate layer that facilitates information transfer between cortical and subcortical DMNs. We studied 180 healthy old adults (aged 64-68 years), who underwent comprehensive assessment of EM, along with resting-state fMRI. We found greater FC between MTL and RSC than between MTL and the other cortical DMN regions (e.g., PCC), with the only significant association with EM observed for MTL-RSC FC. Mediational analysis showed that MTL-cortical DMN connectivity increased with RSC as a mediator. Further analysis using a graph-theoretical approach on DMN nodes revealed the highest betweenness centrality for RSC, confirming that a high proportion of short paths among DMN regions pass through RSC. Importantly, the degree of RSC mediation was associated with EM performance, suggesting that individuals with greater mediation have an EM advantage. These findings suggest that RSC forms a critical gateway between MTL and cortical DMN to support EM in older adults.

“…A few resting‐state fMRI (rsfMRI) studies in AD have parcellated the PMC to examine its intrinsic functional architecture, however most have used a priori defined cortical seed regions to characterise its complex functional neuroanatomy (Cauda et al, ; Dillen et al, ; Margulies et al, ; Wu et al, ). Recent work has highlighted the advantages of connectivity‐based parcellation methods for a more detailed insight into the organisation of regional specialisation of brain regions (Eickhoff, Thirion, Varoquaux, & Bzdok, ; Thirion, Varoquaux, Dohmatob, & Poline, ).…”

Section: Introductionmentioning

confidence: 99%

The heterogeneous functional architecture of the posteromedial cortex is associated with selective functional connectivity differences in Alzheimer's disease

Khan

Amad

Giampietro

et al. 2019

The posteromedial cortex (PMC) is a key region involved in the development and progression of Alzheimer's disease (AD). Previous studies have demonstrated a heterogenous functional architecture of the region that is composed of discrete functional modules reflecting a complex pattern of functional connectivity. However, little is understood about the mechanisms underpinning this complex network architecture in neurodegenerative disease, and the differential vulnerability of connectivity‐based subdivisions in the PMC to AD pathogenesis. Using a data‐driven approach, we applied a constrained independent component analysis (ICA) on healthy adults from the Human Connectome Project to characterise the local functional connectivity patterns within the PMC, and its unique whole‐brain functional connectivity. These distinct connectivity profiles were subsequently quantified in the Alzheimer's Disease Neuroimaging Initiative study, to examine functional connectivity differences in AD patients and cognitively normal (CN) participants, as well as the entire AD pathological spectrum. Our findings revealed decreased functional connectivity in the anterior precuneus, dorsal posterior cingulate cortex (PCC), and the central precuneus in AD patients compared to CN participants. Functional abnormalities in the dorsal PCC and central precuneus were also related to amyloid burden and volumetric hippocampal loss. Across the entire AD spectrum, functional connectivity of the central precuneus was associated with disease severity and specific deficits in memory and executive function. These findings provide new evidence showing that the PMC is selectively impacted in AD, with prominent network failures of the dorsal PCC and central precuneus underpinning the neurodegenerative and cognitive dysfunctions associated with the disease.