Relationship between apathy, glymphatic dysfunction, and white matter integrity in Parkinson's disease: a multimodal MRI study

Apathy is a disabling non-motor symptom of Parkinson's disease (PD), but its neuroimaging correlates remain unclear. Glymphatic-related MRI metrics abnormalities and white matter microstructural damage have each been implicated in PD, yet their relationship with apathy is incompletely understood.

To investigate the relationships among glymphatic-related MRI metrics, white matter abnormalities, and apathy in PD, while accounting for affective, cognitive, motor, and treatment-related factors.

We prospectively enrolled 41 patients with PD [19 with apathy (APD), 22 without apathy (nAPD)] and 38 healthy controls (HC). Multimodal MRI quantified choroid plexus volume (CPV), perivascular space measures, DTI-ALPS, gBOLD-CSF coupling, free water (FW), free-water-corrected diffusion indices, and NODDI metrics. Tract-based spatial statistics, sparse principal component analysis, partial correlation, sensitivity analyses, and exploratory mediation analyses were performed.

Compared with HC, PD patients showed widespread white matter abnormalities, including increased FW, fwAD, fwMD, fwRD, and ODI and decreased fwFA and NDI. APD patients showed higher FW than nAPD patients in clusters involving the corpus callosum, left superior longitudinal fasciculus, uncinate fasciculus, inferior fronto-occipital fasciculus, and other widespread tracts. Within PD, these FW abnormalities were associated with apathy severity; several associations persisted after adjustment for UPDRS-III and levodopa equivalent daily dose but were attenuated after adjustment for affective or cognitive symptoms. CPV measures were also associated with apathy-related FW abnormalities, with selected associations remaining after adjustment for MoCA or motor/medication measures. Direct associations between individual glymphatic-related MRI metrics and apathy severity were less consistent. Exploratory mediation effects were observed mainly in the combined PD + HC cohort and were not robust within PD or apathy subgroups after multiple-comparison correction.

Apathy in PD was most consistently associated with increased extracellular FW within distributed white matter networks, superimposed on widespread PD-related microstructural damage. Glymphatic-related MRI metrics abnormalities, particularly CPV, were coupled with apathy-related FW but showed weaker direct relationships with apathy severity. These findings support an associative glymphatic-white matter framework for PD apathy, while suggesting partial overlap with broader affective and cognitive dysfunction rather than an apathy-specific causal cascade.