Hybrid resting state structural connectome reveals disruption of excitation‐inhibition balance in APOE ε4 carriers

Abstract

AbstractBackgroundMultimodal neuroimaging modalities may improve detection of early brain changes associated with Alzheimer’s disease (AD). We investigated cognitively intact middle‐aged individuals to determine whether male and female APOE‐ε4 carriers demonstrate altered connectivity using a novel multimodal connectomics technique to probe excitation‐inhibition balance.MethodFor 38 cognitively intact APOE‐ε4 carriers aged 40‐60 (μ=50.8) and 38 age (μ=50.9) and sex‐matched (16M/22F) non‐carriers, imaging included: T1‐weighted MRI, resting‐state fMRI and diffusion‐weighted MRI (Korthauer et al, 2018. NeuroImage, 178, 295‐305). Functional connectomes (rs‐FC), constructed with 80 regions of interest (ROIs) used correlation‐based methods on BOLD activity. The hybrid resting state structural connectomes (rs‐SC), constructed using a recently proposed multimodal connectome technique, leverages statistical mechanics to infer connectome‐level excitation‐inhibition balance (Fortel et al, 2019. MICCAI Conference. 503‐511, Springer). Positive edges in this rs‐SC indicate excitatory relationships between ROI pairs, while negative indicate inhibitory relationships. For each ROI, a hyperexcitation indicator (HI) was defined as the percentage of positive edges.ResultUsing rs‐SC and rs‐FC, figure 1 presents a comparison for each sex between group‐averaged HI for ROIs of carriers and non‐carriers. For each sex, we compared carriers and non‐carriers using 2‐sample T‐tests. Functional connectivity shows no significant difference for percentage of positive BOLD correlations for both genders (P > 0.05). By contrast, using rs‐SC, females have a significant increase in HI compared to non‐carriers (P < 0.001), suggesting female APOE‐ε4 carriers have globally disrupted E‐I balance that may confer greater vulnerability to AD neuropathology. Figure 1. Average HI for each ROI computed using the rs‐SC (1A) and rs‐FC (1B). Line x = y is a reference for equal HI between groups. While a strong linear relationship exists between carriers and non‐carriers for both genders using functional connectivity, the HI is comparable. Using rs‐SC, female ε4 carriers show a significant increase in HI compared to non‐carriers.ConclusionWe demonstrated a global shift towards hyperexcitation in a group of cognitively intact female ε4 carriers, less so in the male carriers. Our findings are consistent with known AD sex differences, suggesting that novel multimodal connectomics may capture subtle disruptions in brain dynamics that traditional methods may not.