Objective: To investigate functional alterations of the glia limitans and the consequent changes in glymphatic system dynamics and CD4⁺ T cell infiltration in the disease-affected motor cortex and the comparatively spared occipital cortex.

Background: Glia limitans, including perivascularis and superficialis, plays a critical role in maintaining astrocytic basement membranes and regulating glymphatic function. However, the detailed morphological and functional alterations of the glia limitans, as well as the downstream changes in the perivascular space (PVS) and in CD4⁺ T cell infiltration in Parkinson’s disease (PD) and multiple system atrophy (MSA), remain poorly understood.

Method: Immunofluorescence and digital image analyses were performed on formalin-fixed paraffin-embedded sections of post-mortem motor cortex tissue and occipital cortex tissue. Complementary clinical neuroimaging data were assessed from another cohort of controls, PD, and MSA to evaluate glymphatic system function.

Results: Both the glia limitans perivascularis and glia limitans superficialis exhibited structural and functional abnormalities in PD and MSA. Converging pathological and neuroimaging evidence pointed to dysfunction of the glymphatic system, most prominently in the motor cortex. Immunofluorescence analyses further revealed increased CD4⁺ T cell infiltration in the motor cortex of PD and MSA cases, in contrast to compensatory limitans changes observed in the occipital cortex. Collectively, these findings suggest a bidirectional interplay between glia limitans integrity and glymphatic function, as well as heightened CD4⁺ T cell trafficking in these synucleinopathies, driven by compromised glia limitans.

Conclusion: The functional alterations in the glia limitans, along with disruptions in the glymphatic system and enhanced CD4⁺ T cell trafficking, highlight a previously unrecognized pathomechanistic link between the central nervous system and the peripheral immune system in synucleinopathies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/altered-glia-limitans-structure-and-function-in-parkinsons-disease-and-multiple-system-atrophy/