The Role of Hub and Spoke Regions in Theory of Mind in Early Alzheimer's Disease and Frontotemporal Dementia.

Beatrice Orso,Enrico Peira,Erica Biassoni,Dario Arnaldi,Andrea Brugnolo,Flavio Nobili,Silvia Morbelli,Luigi Lorenzini,Elisa Doglione,Maria I Donegani,Matteo Pardini,Federico Massa,Nicola Girtler,Matteo Bauckneht,Pietro Mattioli

doi:10.3390/biomedicines10030544

Abstract

Theory of mind (ToM, the ability to attribute mental states to others) deficit is a frequent finding in neurodegenerative conditions, mediated by a diffuse brain network confirmed by 18F-FDG-PET and MR imaging, involving frontal, temporal and parietal areas. However, the role of hubs and spokes network regions in ToM performance, and their respective damage, is still unclear. To study this mechanism, we combined ToM testing with brain 18F-FDG-PET imaging in 25 subjects with mild cognitive impairment due to Alzheimer’s disease (MCI–AD), 24 subjects with the behavioral variant of frontotemporal dementia (bvFTD) and 40 controls. Regions included in the ToM network were divided into hubs and spokes based on their structural connectivity and distribution of hypometabolism. The hubs of the ToM network were identified in frontal regions in both bvFTD and MCI–AD patients. A mediation analysis revealed that the impact of spokes damage on ToM performance was mediated by the integrity of hubs (p < 0.001), while the impact of hubs damage on ToM performance was independent from the integrity of spokes (p < 0.001). Our findings support the theory that a key role is played by the hubs in ToM deficits, suggesting that hubs could represent a final common pathway leading from the damage of spoke regions to clinical deficits.

Highlights

We focused on mild cognitive impairment due to Alzheimer’s disease (AD) (MCI–AD) and on behavioral variant frontotemporal dementia patients, given the differences in the neurodegeneration distribution pattern between these two conditions
To go into more detail, combining a widely used Theory of Mind (ToM) test and brain 18 F-FDG-PET, we evaluated whether hub regions played a more significant role on ToM performance than spoke regions, and if the impact of spoke regions damage on ToM performance was mediated by the extent of degeneration in the hubs
The RMET regions of interest (ROIs) included in the areas of relative hypometabolism in mild cognitive impairment due to Alzheimer’s disease (MCI–AD) group were the left cingulate gyrus, right superior frontal gyrus, right middle frontal gyrus, left middle temporal gyrus, and right superior temporal gyrus (Figure 2B)

Summary

Introduction

An open question remains regarding the relative importance of each of these regions in leading to ToM deficits across different clinical conditions and the ability of functional imaging to capture those changes more relevant to ToM performance in the earliest phases of the neurodegenerative process. Studies using brain 18 F-fluorodeoxyglucose positron emission tomography (18 F-FDG-PET) and tau markers have shown a negative correlation between tau deposition and cerebral metabolism in the right temporal, parietal and frontal lobes in a cohort of 100 Alzheimer’s disease (AD) patients, confirming the clinical relevance of these regions in AD and suggesting that functional imaging can capture degeneration in these areas in AD [7,8].

Methods

Results

Conclusion