Objective: This study explored longitudinal changes in cellular inflammatory, autophagic mediators in L1CAM and TMEM119-enriched exosomal samples of patients with Parkinson’s disease (PD) and Progressive Supranuclear Palsy (PSP).

Background: PD and PSP lack reliable, non-invasive biomarkers for diagnosis and disease monitoring. Multiple cell types, including neurons, astrocytes and microglia, have been found to release exosomes. Exosomes’ ability to carry material that can influence recipient cell’s activity, highlights their potential as reliable and sensitive biomarkers. Thus, accurate detection and monitoring of disease progression of PD and PSP through exosome markers would be highly relevant for drug development.

Method: Serum samples of 30 PD, 20 PSP and 30 healthy controls were collected at baseline and 1 year follow-up. Serum extracellular vesicles were isolated and immunoprecipitated by targeting the neuronal marker(L1CAM), microglial marker (TMEM119). Cellular inflammatory (NLRP3, IL-1ß, TLR2), autophagic (pmTOR/mTOR, pNF-κB/NF-κB, ATP6AP2) mediators and phospho Alpha-Syn/ Total Alpha-Syn were assessed and compared with the levels of crude serum samples. Kruskal-Wallis test with correction for multiple comparisons was performed to validate these findings between groups.

Results: L1CAM and TMEM119-enriched exosomes had elevated expression of ATP6AP2, pmTOR/mTOR, pNF-κB/NF-κB, phospho/Total Alpha-Syn in PD and PSP compared to control (p<0.01). In PD and PSP patients, serum NLRP3 inflammasome and IL-1β levels increased significantly over 1 year compared to baseline, whereas markers like pmTOR/mTOR, pNF-κB/NF-κB, ATP6AP2 significantly differentiated between PD and PSP (p<0.01). ROC curve of NLRP3, IL-1ß and ATP6AP2 between PD and PSP demonstrated its diagnostic utility (AUC 0.78, 0.77, 0.72 respectively) (p<0.05).

Conclusion: To our understanding, for the first time this longitudinal study with L1CAM and TMEM119-enriched exosomes explored cellular inflammatory and autophagic mediators in PD and PSP. Markers like pmTOR/mTOR, pNF-κB/NF-κB, ATP6AP2 differentiated between PD and PSP validating its specificity. This study also highlighted the sensitivity and specificity of using exosomal biomarkers compared to non-specific serum/plasma markers. Finally, Large cohort studies with varied cell-based markers are needed to validate these potential peripheral biomarkers in PD and PSP.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/l1cam-and-tmem119-enriched-exosomal-markers-in-parkinsons-disease-and-progressive-supranuclear-palsy-a-prospective-study/