Glymphatic dysfunction exacerbates cognitive decline by triggering cortical degeneration in Parkinson's disease: evidence from diffusion-tensor MRI

The glymphatic system may play a central role in cognitive impairment associated with Parkinson's disease, but its relationship with regional cortical atrophy is not fully explored. To explore associations among glymphatic dysfunction, regional cortical degeneration and cognitive impairment in Parkinson's disease participants, we evaluated 51 participants with documented Parkinson's disease (28 men; age, 61.65 ± 8.27 years) and 30 age- and sex-matched normal controls (11 men; age, 59.2 ± 5.90 years) who underwent 3.0-T MRI of the brain, including high-resolution T1-weighted imaging and diffusion-tensor imaging along the perivascular space as a surrogate for glymphatic flow. Cortical grey matter volume was segmented automatically based on three-dimensional T1-weighted sequences. Cognitive function was assessed by Mini-Mental State Examination. The relationship between glymphatic dysfunction, cognitive decline and regional cortical degeneration was explored. The participants with Parkinson's disease revealed lower diffusion-tensor imaging along the perivascular space (1.45 ± 0.17 versus 1.64 ± 0.17, <i>P</i> < 0.0001) as compared with normal controls, indicating disturbed glymphatic flow. Glymphatic dysfunction was associated with cognitive scores (<i>r</i> = 0.54, <i>P</i> = 0.003). Diffusion-tensor imaging along the perivascular space values were positively associated with the volume of specific cortical regions (all <i>P</i>-values <0.05) including the temporal pole, posterior orbital gyrus, orbital part of the inferior frontal gyrus, frontal operculum, central operculum and anterior cingulate gyrus. Mediation analysis within the Parkinson's disease participants indicated that the relationship between glymphatic dysfunction and cognitive scores was partially mediated by the integrity of orbital part of the inferior frontal gyrus and anterior cingulate gyrus. Glymphatic dysfunction is associated with cognitive decline in Parkinson's disease, whereas the distribution of regional cortical degeneration may constitute the link between glymphatic dysfunction and cognitive impairment.