Glymphatic function from diffusion-tensor MRI to predict conversion from mild cognitive impairment to dementia in Parkinson's disease

Abstract

Background: Although brain glymphatic dysfunction is a contributing factor to the cognitive deficits in Parkinson's disease (PD), its role in the longitudinal progression of cognitive dysfunction remains unknown.

Objective: To investigate the glymphatic function in PD with mild cognitive impairment (MCI) that progresses to dementia (PDD) and to determine its predictive value in identifying individuals at high risk for developing dementia.

Methods: We included 64 patients with PD meeting criteria for MCI and categorized them as either progressed to PDD (converters) (n = 29) or did not progress to PDD (nonconverters) (n = 35), depending on whether they developed dementia during follow-up. Meanwhile, 35 age- and gender-matched healthy controls (HC) were included. Bilateral diffusion-tensor imaging analysis along the perivascular space (DTI-ALPS) indices and enlarged perivascular spaces (EPVS) volume fraction in bilateral centrum semiovale, basal ganglia (BG), and midbrain were compared among the three groups. Correlations among the DTI-ALPS index and EPVS, as well as cognitive performance were analyzed. Additionally, we investigated the mediation effect of EPVS on DTI-ALPS and cognitive function.

Results: PDD converters had lower cognitive composites scores in the executive domains than did nonconverters (P < 0.001). Besides, PDD converters had a significantly lower DTI-ALPS index in the left hemisphere (P < 0.001) and a larger volume fraction of BG-PVS (P = 0.03) compared to HC and PDD nonconverters. Lower DTI-ALPS index and increased BG-PVS volume fraction were associated with worse performance in the global cognitive performance and executive function. However, there was no significant mediating effect. Receiver operating characteristic analysis revealed that the DTI-ALPS could effectively identify PDD converters with an area under the curve (AUC) of 0.850.

Conclusion: The reduction of glymphatic activity, measured by the DTI-ALPS, could potentially be used as a non-invasive indicator in forecasting high risk of dementia conversion before the onset of dementia in PD patients.

Keywords: Cognitive impairment; Dementia conversion; Glymphatic function; Parkinson’s disease; Perivascular space.

Fig. 1

Flowchart of patient inclusion and exclusion criteria. PD-MCI Parkinson’s disease with mild cognitive impairment

Fig. 2

Schematic diagram of the DTI-ALPS index and PVS volume evaluation. (Upper) (left) ROIs on the projection fibers (blue) and association fibers (green), drawn on the colored FA map. (Right) spatial correlation between the perivascular space and subcortical fibers (red; x-axis), association fibers (green; y-axis), and projection fibers (blue; z-axis). (Below) T2-weighted images and PVS mask in the area of basal ganglia (left; red), centrum semiovale (middle, blue), and the level of lateral ventricle body (right, yellow).

Fig. 3

Differences in left DTI-ALPS, diffusivities, and PVS volume fraction among HC, PDD converters, and PDD nonconverters using the Kruskal–Wallis H test followed by a post hoc Dunnett T3 test. *P < 0.05, **P < 0.01, ***P < 0.001, statistically significant under false discovery rate adjustment

Fig. 4

Partial correlations among the left DTI-ALPS index, BG-PVS volume fraction, and cognitive performance after adjustments for age, sex, and years of education

Fig. 5

ROC analyses of the left DTI-ALPS index, diffusivities, and BG-PVS