Impaired glymphatic clearance independently contributes to poor outcomes in Parkinsons disease

Zarkali, A.; Thomas, G. E. C.; Patterson, R.; Hannaway, N.; Dobreva, I.; Heslegrave, A.; Veleva, E.; Zetterberg, H.; Weil, R. S.

doi:10.1101/2025.01.15.633106

bioRxiv · 10.1101/2025.01.15.633106

Impaired glymphatic clearance independently contributes to poor outcomes in Parkinsons disease

Zarkali, A.·Thomas, G. E. C.·Patterson, R.·Hannaway, N.·Dobreva, I.·Heslegrave, A.·Veleva, E.·Zetterberg, H.·Weil, R. S.

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Abstract

BackgroundImpaired glymphatic clearance may contribute to pathological accumulations in Parkinsons (PD), but how it interacts with other processes causing dementia and poor outcomes remains unclear. ObjectivesClarify how glymphatic clearance impacts cognition in PD and its interaction with established imaging markers. MethodsWe used diffusion tensor image analysis along the perivascular space (DTI-ALPS) as an indirect marker of glymphatic clearance in 98 PD patients (31 PD-poor outcomes: dementia, mild cognitive impairment, frailty or death within 3-year follow-up; 67 PD-good outcomes) and 28 controls. We assessed DTI-ALPS relationship to cognition, white matter (fibre cross-section), cortical thickness, iron accumulation (quantitative susceptibility mapping (QSM)), and plasma markers (phosphorylated tau-181 (p-tau181 and neurofilament light (NFL)) cross-sectionally and longitudinally. ResultsDTI-ALPS was lower in PD-poor outcomes compared to PD-good outcomes and controls (p=0.005) with further longitudinal reductions only in PD-poor outcomes (group*time interaction: {beta}=-0.013, p=0.021). Lower DTI-ALPS was associated with lower fibre cross-section in P, at baseline and longitudinally but with different spatial distribution from white matter changes relating to PD cognition. There was no correlation between baseline DTI-ALPS and plasma ptau-181 (p=0.642), NFL (p=0.448) or baseline cortical thickness. Lower DTI-ALPS was associated with accelerated cortical thinning within left precentral gyrus and changes in brain iron distribution. ConclusionsPD patients who develop poor outcomes show impaired glymphatic clearance at baseline that worsened longitudinally. DTI-ALPS correlated with white matter integrity and brain iron accumulation. However, both showed different spatial distribution than that seen in PD dementia; suggesting impaired glymphatic clearance contributes to cognitive decline in a distinct manner.

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Zarkali, A., Thomas, G. E. C., Patterson, R., Hannaway, N., Dobreva, I., Heslegrave, A., Veleva, E., Zetterberg, H., Weil, R. S.. 2025-01-17. Impaired glymphatic clearance independently contributes to poor outcomes in Parkinsons disease. https://doi.org/10.1101/2025.01.15.633106

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