Spatial correspondence between altered brain function and normative neurotransmitter density maps in Type 1 diabetes...

Type 1 diabetes mellitus (T1DM) is associated with cognitive impairment, yet the underlying neurobiological mechanisms remain poorly understood. While resting-state functional magnetic resonance imaging (rs-fMRI) has revealed aberrant brain activity in T1DM, the spatial correlation between these functional alterations and normative neurotransmitter receptor/transporter distributions has not been systematically explored.

We enrolled 43 T1DM patients and 52 well-matched healthy controls (HCs). All participants underwent rs-fMRI and comprehensive neuropsychological assessments. We analyzed spontaneous neural activity using the amplitude of low-frequency fluctuations (ALFF) and inter-hemispheric functional coordination using voxel-mirrored homotopic connectivity (VMHC). The spatial correlation between brain activity patterns and normative neurotransmitter receptor/transporter distributions was assessed using the JuSpace toolbox.

Compared to HCs, T1DM patients demonstrated poorer overall cognitive performance. Neuroimaging analyses revealed significantly decreased ALFF in the right thalamus and increased VMHC in the bilateral insula. More importantly, the ALFF reduction showed spatial overlap with the distributional regions of serotonergic (SERT), dopaminergic (D2, DAT), GABAergic (GABAa), opioid (MOR), glutamatergic (NMDA), and cholinergic (VAChT) systems. The VMHC increase showed spatial overlap with the distributional regions of the serotonergic system (SERT, 5-HT4). Most spatial associations were replicated across atlases, although the D2 and GABAa findings were not. Furthermore, right thalamic ALFF negatively correlated with HbA1c levels.

This study demonstrates spatial correspondences between T1DM-related brain functional alterations and normative distributions of multiple neurotransmitter receptors/transporters. The negative correlation between thalamic ALFF and HbA1c suggests an association between chronic hyperglycemia and local brain activity. These findings offer a novel perspective on the pathophysiology of cognitive impairment in T1DM.