Relationship of Glymphatic Function with Cognitive Impairment, Sleep Disorders, Anxiety and Depression in Patients with Parkinson's Disease

Abstract

Introduction: Previous studies have predominantly explored the relationship of the glymphatic system with motor symptoms in Parkinson's disease (PD); however, research on non-motor symptoms remains limited. Therefore, this study investigated the association between glymphatic function and non-motor symptoms, including cognitive impairment and sleep disorders, in PD patients.

Methods: This study recruited 49 PD patients and 38 healthy controls (HC). Glymphatic function was evaluated using enlarged perivascular spaces (EPVS) in the basal ganglia (BG) region and diffusion tensor image analysis along the perivascular space (DTI-ALPS) index. Cognition, sleep, anxiety, and depression scales were assessed in all participants. According to the scale scores, PD patients were further divided into several groups to identify the presence of non-motor symptoms. Differences in EPVS numbers and ALPS index between PD subgroups and HC group were compared. Spearman correlation analysis was performed to investigate the association between the PD non-motor symptoms and ALPS index. Additionally, receiver operating characteristic (ROC) curves analysis was conducted for ALPS index to predict cognitive impairment and insomnia in PD patients.

Results: PD patients with and without non-motor symptoms all showed more EPVS numbers than the controls, and the EPVS numbers in PD patients with cognitive impairment were also greater than those without. Notably, except for the depression subgroup, PD patients with non-motor symptoms showed significantly lower ALPS index than the controls. The Montreal Cognitive Assessment (MoCA) scores were positively correlated, whereas the Parkinson's Disease Sleep Scale (PDSS)-2 and REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) scores were negatively correlated with the ALPS index in PD patients (r=0.3618, P=0.0053; r=-0.4146, P=0.0015; r=-0.2655, P=0.0326, respectively). The ALPS index proved to be predictive of cognitive impairment and insomnia in PD patients (AUC=0.7733, P=0.001; AUC=0.7993, P=0.0004, respectively).

Conclusion: Glymphatic function is closely associated with cognition and sleep of PD patients.

Keywords: cognition; glymphatic system; non-motor symptoms; parkinson’s disease; sleep.

Figure 1

Schematic diagram of the glymphatic system and DTI-ALPS methodology. (A) As described in the introduction section, the glymphatic system drives the bulk fluid flow from periarterial spaces to perivenous spaces to clear large solutes. (B) On the left, colored FA map shows ROIs on the subcortical fibers (red), association fibers (green), and projection fibers (blue) in bilateral hemispheres. On the right, the spatial relationships among the perivascular space, subcortical fibers (red; x-axis), association fibers (green; y-axis), and projection fibers (blue; z-axis) are showed. The formula of the DTI-ALPS index is showed on the left side.

Figure 2

Comparisons of the BG-EPVS numbers in different groups using violin graphs.(A) Comparisons of the BG-EPVS numbers among the PD-NC, PD-CI, and HC groups. (B) Comparisons of the BG-EPVS numbers among the PD-NI, PD-I, and HC groups. (C) Comparisons of the BG-EPVS numbers among the PD-NEDS, PD-EDS, and HC groups. (D) Comparisons of the BG-EPVS numbers among the PD-NRBD, PD-RBD, and HC groups. (E) Comparisons of the BG-EPVS numbers among the PD-NA, PD-A, and HC groups. (F) Comparisons of the BG-EPVS numbers among the PD-ND, PD-D, and HC groups. *indicates p value < 0.05; **indicates p value < 0.01; ***indicates p value < 0.001.

Figure 3

Comparisons of the ALPS index in different groups using violin graphs, and ROC curves analyses for the ALPS index to predict cognitive impairment and insomnia (A) Comparison of the ALPS index between the PD and HC group. (B) Comparisons of the ALPS index among the PD-NC, PD-CI, and HC groups. (C) Comparisons of the ALPS index among the PD-NI, PD-I, and HC groups. (D) Comparisons of the ALPS index among the PD-NEDS, PD-EDS, and HC groups. (E) Comparisons of the ALPS index among the PD-NRBD, PD-RBD, and HC groups. (F) Comparisons of the ALPS index among the PD-NA, PD-A, and HC groups. (G) Comparisons of the ALPS index among the PD-ND, PD-D, and HC groups. (H) ROC curve was used to evaluate the diagnostic accuracy of the ALPS index to discriminate PD patients with and without cognitive impairment. (I) ROC curve was used to evaluate the diagnostic accuracy of the ALPS index to discriminate PD patients with and without insomnia. *indicates p value < 0.05; **indicates p value < 0.01; ***indicates p value < 0.001.

Figure 4

Correlations between cognitive impairment, insomnia, EDS, RBD, anxiety, depression and ALPS index in PD patients. (A–F) Correlations of the MoCA, PDSS-2, ESS, RBDSQ, HAMA, and HAMD scores with ALPS index in PD group. *indicates p value < 0.05; **indicates p value < 0.01; ***indicates p value < 0.001.