Altered Interplay Among Large-Scale Brain Functional Networks Modulates Multi-Domain Anosognosia in Early Alzheimer's Disease

Decline in self-awareness is a prevalent symptom in Alzheimer's disease (AD). Current data suggest that an early breakdown in the brain's default mode network (DMN) is closely associated with the main symptomatic features in AD patients. In parallel, the integrity of the DMN has been shown to be heavily implicated in retained self-awareness abilities in healthy individuals and AD patients. However, the global contribution to awareness skills of other large-scale networks is still poorly understood. Resting-state functional magnetic resonance imaging (rs-fMRI) scans were acquired and pre-processed from 53 early-stage AD individuals. A group-level independent component analysis was run to isolate and reconstruct four intrinsic connectivity large-scale brain functional networks, namely left and right central executive fronto-parietal networks (FPN), salience network, and anterior and posterior DMN. Hypothesis-driven seed-based connectivity analyses were run to clarify the region-specific underpinnings of multi-domain anosognosia. Multiple regression models were run on large-scale network- and seed-based connectivity maps, including scores of memory, non-memory and total anosognosia obtained via the Measurement of Anosognosia Questionnaire. Memory anosognosia scores were associated with selective lower fronto-temporal connectivity and higher parieto-temporal connectivity. Non-memory anosognosia scores were associated with higher connectivity between the anterior DMN and the cerebellum, between the left medial prefrontal seeds and the contralateral prefrontal cortex, and between the left hippocampal seed and the left insula; lower connectivity was observed between the right prefrontal cortex and the right lingual seed. Lastly, total anosognosia scores were associated with large-scale network alterations, namely reduced left-FPN expression in the left posterior cingulate, reduced right-FPN expression in the left inferior lingual gyrus and adjacent inferior occipital cortex, and increased right-FPN expression in the right anterior cingulate. Seed-based analyses yielded significant connectivity differences only in the connectivity pattern associated with the left hippocampal seed by displaying lower intercommunication with the right prefrontal cortex, but higher connectivity with the left caudate nucleus. These findings support the hypothesis that alterations in functional connectivity of frontal lobe regions involved in executive-related mechanisms represent the neural correlates of domain-specific anosognosia in early AD. Up-regulated connectivity with subcortical structures appears to contribute to changes in the network dynamics interplay and fosters the appearance of anosognosia.

Automated summary

Decline in self-awareness is a common symptom in Alzheimer's disease, and it is closely associated with the early breakdown of the brain's default mode network. The contribution of other large-scale networks to self-awareness abilities is still poorly understood. The study found that memory anosognosia in early-stage AD patients is associated with decreased fronto-temporal connectivity and increased parieto-temporal connectivity. Non-memory anosognosia is associated with increased connectivity between the anterior default mode network and the cerebellum, as well as increased connectivity between specific seeds in the left medial prefrontal cortex and the contralateral prefrontal cortex. Total anosognosia is associated with alterations in large-scale networks, including reduced expression of the left central executive fronto-parietal network in the left posterior cingulate and increased expression in the right anterior cingulate. Seed-based analyses showed significant connectivity differences in the left hippocampal seed, indicating lower intercommunication with the right prefrontal cortex and higher connectivity with the left caudate nucleus. These findings suggest that alterations in functional connectivity of frontal lobe regions involved in executive-related mechanisms are associated with domain-specific anosognosia in early AD.