The Abnormal Accumulation of Pathological Proteins and Compensatory Functional Connectivity Enhancement of Insula Subdivisions in Mild Cognitive Impairment

Darui Zheng ¹ Chen Xue ¹ Yingcai Feng ² Yiming Ruan ¹ Wenzhang Qi ¹ Qianqian Yuan ¹ Zonghong Li ^1* Chaoyong Xiao ^1*

• ¹ Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China
• ² Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China

The insula is a critical node of the salience network responsible for initiating network switching, and its dysfunctional connections are linked to the mechanisms of mild cognitive impairment (MCI). This study aimed to explore the changes in functional connectivity (FC) of insular subregions in MCI patients with varying levels of cerebrospinal fluid (CSF) pathological proteins, and to investigate the impact of these proteins on the brain network alterations in MCI.Methods: Based on CSF Amyloid-beta (Aβ, A) and phosphorylated tau protein (p-tau, T), MCI patients were classified into 54 A-T-, 28 A+T-, and 52 A+T+ groups. Seedbased FC analysis was employed to compare the FC differences of insular subregions across the three groups. Correlation analysis was further conducted to explore the relationship between altered FC and cognitive function. Finally, ROC curve analysis was used to assess the diagnostic value of altered FC of insular subregion in distinguishing between the groups.In the left ventral anterior insula, left dorsal anterior insula, and bilateral posterior insular subnetworks, both the A+T-and A+T+ groups showed increased FC compared to the A-T-group, with the A+T+ group showing further increased FC compared to the A+T-group. Additionally, FC of the left cerebellar posterior lobe was negatively correlated with RAVLT-learning, and FC of the left middle frontal gyrus was negatively correlated with p-tau levels. Finally, logistic regression analysis demonstrated that multivariable analysis had high sensitivity and specificity in distinguishing between the groups.This study showed that MCI patients with abnormal CSF pathological protein levels exhibit compensatory increases in FC of insular subregions, which in turn affect cognitive function. Our findings contributed to a better understanding of the pathophysiology and underlying neural mechanisms of MCI.