# Association Between Glymphatic Function and White Matter Microstructural Injury in Patients With Cushing's Disease

## TL;DR

This study shows that glymphatic dysfunction in Cushing's disease patients is linked to white matter injury, especially in the right superior longitudinal fasciculus III.

## Contribution

This is the first study to demonstrate glymphatic functional impairment in Cushing's disease and its mediating role in white matter injury.

## Key findings

- CD patients had significantly reduced glymphatic function compared to healthy controls.
- Impaired glymphatic function fully mediated the effect of elevated midnight cortisol on white matter injury in the SLF III_R.
- Widespread white matter microstructural injury was observed in CD patients, with decreased FA and increased MD across multiple tracts.

## Abstract

Patients with Cushing's disease (CD) exhibit white matter (WM) microstructural injury, yet the underlying mechanisms remain incompletely understood. This study aims to investigate the role of glymphatic function in WM damage among patients with CD.

A total of 69 patients with CD and 64 healthy controls(HC) were enrolled. Glymphatic system function was evaluated using the diffusion tensor image analysis along the perivascular space (DTI‐ALPS) index. WM microstructural injury across 42 tracts was assessed via fractional anisotropy (FA) and mean diffusivity (MD). Serum cortisol levels were quantified using chemiluminescence immunoassay.

Compared with HC, patients with CD exhibited significantly reduced DTI‐ALPS indices (p = 0.026). Widespread WM microstructural injury was observed, characterized by decreased FA in 25 tracts and increased MD in 40 tracts. Correlation analyses revealed that in patients with CD, the DTI‐ALPS index showed a significant positive correlation with FA values of the right superior longitudinal fasciculus III (SLF III_R; r = 0.42, p = 0.033) and a significant negative correlation with 00:00 cortisol levels (r = −0.354, p = 0.004). Furthermore, mediation analysis confirmed that the DTI‐ALPS index fully mediated the effect of 00:00 cortisol level on the reduction of FA in the SLF III_R (ACME = −0.138, 95% CI: [−0.319, −0.013], p = 0.021).

This study provides the first evidence of glymphatic functional impairment in patients with CD. Our findings suggest that aberrantly elevated midnight cortisol levels serve as a primary driver of this glymphatic functional impairment. Furthermore, this impaired glymphatic function fully mediates the impact of 00:00 cortisol levels on microstructural injury to the SLF III_R.

This study suggests that glymphatic dysfunction is associated with white matter injury in Cushing's disease. Mediation analysis indicates that impaired glymphatic function may serve as a pathway linking elevated midnight cortisol to structural damage in the right superior longitudinal fasciculus III.