Papez circuit remodeling in type 2 diabetes: Enlarged choroid plexus volume partially mediates functional impairments linked to insulin resistance.

AIM: Type 2 diabetes mellitus (T2DM) is a metabolic disorder associated with cognitive decline. This study investigated the interplay between altered effective connectivity (EC) in the Papez circuit, regional atrophy, and choroid plexus volume (CPV) in relation to T2DM-related cognitive deficits.

METHODS

Eighty T2DM patients and 75 healthy controls underwent multimodal MRI. Resting-state fMRI data were analyzed using spectral dynamic causal modeling (spDCM) to quantify EC between Papez circuit regions. Structural 3D-T1 images were processed to measure regional volumes and the CPV, which might serve as a proxy for glymphatic activity. Participants underwent standardized cognitive assessments to evaluate neurocognitive function.

RESULTS

T2DM patients exhibited significant EC reductions in three Papez circuit pathways: from the hippocampus (HPC) to the mammillary body (MB) (p = 0.001), from the anterior thalamic nucleus (AT) to the anterior cingulate cortex (ACC) (p = 0.005), and from the entorhinal cortex (ERC) to the HPC (p < 0.001). Structural atrophy was observed in the left hippocampus (p = 0.001) and left thalamic (p = 0.006), accompanied by CPV enlargement (p = 0.027). Notably, the HPC to MB connectivity was partially mediated by the CPV, with a significant indirect effect of 0.1456 (95 % CI: 0.0335, 0.2665). The Complex Figure Test delay (CFT-delay) score was positively correlated with the reduced EC in Papez circuit pathways; however, there was a negative correlation between the CFT-delay score and the CPV (r = -0.344, p = 0.002). Furthermore, reduced EC in the Papez circuit exhibited a negative correlation with the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR).

CONCLUSION

Our study highlights the complex interplay between Papez circuit functional disruptions, structural atrophy within the circuit, as well as the CPV alterations in T2DM-related cognitive decline. These findings offer potential biomarkers for early detection of cognitive impairments and novel therapeutic targets for intervention in T2DM.