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

Abstract

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.

Simultaneous PET/fMRI Detects Distinctive Alterations in Functional Connectivity and Glucose Metabolism of Precuneus Subregions in Alzheimer’s Disease

“…To the best of our knowledge, disrupted FCS within V_pcu (or any subregions of the precuneus), as a reflection of local intrinsic FC, has not been previously reported. Disrupted global FC between V_pcu and other brain regions has been consistently shown by studies investigating differential functional architecture of the subregions of the posteromedial cortex (PMC) affected by AD (Xia et al, 2014;Wu et al, 2016;Khan et al, 2020). Among them, Wu et al (2016) reported that disruptions began in a transitional region between the posterior cingulate cortex (PCC) and precuneus, which has an overlap with the V_pcu in this study, in mild AD patients and then spread to other subregions of PMC as the disease became more severe.…”

“…Abbreviations: FSC, functional connectivity strength; SUVR, standard uptake value ratio; CN, cognitively normal; MCI, mild cognitive impairment; AD, Alzheimer's Disease; V_pcu, ventral precuneus; DP_pcu, dorsal posterior precuneus; DA_pcu, dorsal anterior precuneus; ANOVA, analysis of variance. (Khan et al, 2020). Originated from its cytoarchitecture (Cavanna and Trimble, 2006) and agreed by studies utilizing anatomical (Wang et al, 2019) and functional connectivities (Margulies et al, 2009;Ye et al, 2021) in both humans and macaques, three distinct subregions have been suggested, namely the dorsal-anterior, dorsal-posterior and ventral precuneus.…”

“…Previous studies have demonstrated selective vulnerability of these subregions affected by AD. Specifically, while the ventral/central subregion of the precuneus showed significantly reduced resting-state FC with other brain regions in AD patients, the dorsal subregion was unchanged or slightly disturbed (Xia et al, 2014;Wu et al, 2016;Khan et al, 2020). Nevertheless, how the internal functional integrity of each subregion is affected by AD remains to be elucidated.…”

A Systematic Review of the Association between Amyloid-β and τ Pathology with Functional Connectivity Alterations in the Alzheimer Dementia Spectrum Utilizing PET Scan and rsfMRI

“…Seed-based connectivity was investigated either through all voxels and ROI across the brain or within known networks. In 6 studies applying the first approach, 3 studies indicated a negative correlation between global Aβ depositions and connectivity in AD patients and CN participants [32], all CN–, CN+, and MCI subjects [10], and SMC participants [33], among which 1 work also found a positive correlation when conducting the analysis merely in MCI patients [10]. Two other studies indicated a positive association between Aβ deposition and FC [17, 20].…”

Altered Regional Cerebral Blood Flow and Brain Function Across the Alzheimer's Disease Spectrum: A Potential Biomarker

“…PCC/PCUN, as one of the core regions in the default mode network (DMN), has been widely reported to be associated with a decreased rCBF, disrupted activity, and a destructive brain network in subjects with MCI and subjects with AD (Yoshiura et al, 2009 ; Sierra-Marcos, 2017 ; Xue et al, 2019 ). Notably, functional abnormalities of PCC/PCUN were also associated with the increased amyloid burden and decreased hippocampal volume (Khan et al, 2020 ). Additionally, a recent study, which explored the correlation between an altered rCBF and brain function in AD, revealed that the combination of ASL and the amplitude of low-frequency fluctuations (ALFF) in the PCC/PCUN could be used as a potential biomarker for the diagnosis of AD (Zheng et al, 2019 ).…”