# Longitudinal Neuroimaging Reveals Divergent Clinical Associations of Glymphatic Dysfunction and Dopaminergic Degeneration in Parkinson's Disease

## TL;DR

This study finds that glymphatic dysfunction and dopamine loss in Parkinson's disease are separate processes, each linked to different symptoms and brain changes.

## Contribution

The study identifies glymphatic dysfunction and dopaminergic degeneration as distinct, uncorrelated pathways in Parkinson's disease progression.

## Key findings

- Glymphatic dysfunction (DTI-ALPS) correlates with motor severity and white matter degeneration in Parkinson's disease.
- Dopaminergic degeneration (DAT-SBR) is linked to sleep disorders and non-motor symptoms, independent of glymphatic function.
- Both DTI-ALPS and DAT-SBR are reduced in Parkinson's patients compared to controls and decline further over four years.

## Abstract

To investigate the association between glymphatic function and dopaminergic degeneration in PD assessed via diffusion tensor imaging analysis along the perivascular space (DTI‐ALPS) and dopamine transporter imaging striatal binding ratio (DAT‐SBR), aiming to clarify their controversial relationship and distinct roles in disease progression. A total of 70 early‐stage, drug‐naïve patients with PD and 70 age‐ and sex‐matched healthy controls (HCs) were selected from the Parkinson's Progression Markers Initiative database for cross‐sectional analysis. Longitudinal data at 4‐year follow‐up were available for the PD group. Glymphatic function was evaluated using DTI‐ALPS, and dopaminergic function using DAT‐SBR derived from DAT‐SPECT imaging. Clinical motor and non‐motor assessments were performed at baseline and follow‐up. Correlations between imaging index and clinical variables were analyzed using Spearman correlation and multivariate regression. At baseline, both DTI‐ALPS and DAT‐SBR index were significantly lower in PD patients compared to HCs. Notably, no significant correlation was observed between ALPS and SBR index. Clinically, the DTI‐ALPS index showed negative correlations with body mass index, disease duration, Hoehn and Yahr stage, and UPDRS III scores, and its longitudinal decline correlated with white matter microstructural degeneration. The DAT‐SBR index was negatively correlated with Epworth Sleepiness Scale, REM sleep behavior disorder score, and serum urate. Our findings suggest that glymphatic dysfunction and nigrostriatal denervation represent independent, parallel pathological trajectories in early PD. While the ALPS index may serve as a potential imaging marker of structural network integrity linked to motor execution. These indices offer distinct, complementary mechanistic insights into PD pathology.

Longitudinal PD cohort: ALPS and DAT‐SBR are reduced vs. controls and decline.ALPS and DAT‐SBR show no correlation, indicating distinct pathological pathways.ALPS links to motor severity (UPDRS‐III) and white matter structure, serving as a marker of network integrity.

Longitudinal PD cohort: ALPS and DAT‐SBR are reduced vs. controls and decline.

ALPS and DAT‐SBR show no correlation, indicating distinct pathological pathways.

ALPS links to motor severity (UPDRS‐III) and white matter structure, serving as a marker of network integrity.

Both DTI‐ALPS and DAT‐SBR index in patients with PD were significantly lower compared to Healthy Controls, with further reductions observed at the follow‐up.Both DTI‐ALPS and DAT‐SBR index in PD showed significant correlation with different clinical measures, while no significant correlation was observed between these two index.

Both DTI‐ALPS and DAT‐SBR index in patients with PD were significantly lower compared to Healthy Controls, with further reductions observed at the follow‐up.

Both DTI‐ALPS and DAT‐SBR index in PD showed significant correlation with different clinical measures, while no significant correlation was observed between these two index.