Discovery and Development of Biomarkers for Parkinson’s Disease and Related Disorders

Abstract

The diagnosis and management of Parkinson's Disease (PD) are hindered by the absence of specific biomarkers, necessitating the development of reliable diagnostic and prognostic indicators. Addressing this gap, this thesis explores the discovery of PD biomarkers using targeted and untargeted approaches. Targeted approaches include developing immunoassays for α-synuclein oligomers, which are significant in PD pathology. Using an oligomers-specific anti-α-synuclein antibody, 2A1, the developed assay was promising for measuring α-synuclein oligomers in cerebrospinal fluid, but the assay alone could not adequately differentiate between PD patients and healthy controls. This limitation highlighted the need for assay refinement to a more discerning diagnostic tool. Leveraging the concept of seeding amplification while employing the use of our oligomers-specific ELISA, we developed a novel assay named “Seeding Amplification Immunoassay (SAIA)”. The SAIA had markedly increased the diagnostic sensitivity to disease, showing promise for early PD detection, especially in at-risk populations such as RBD cases and LRRK2 mutation carriers. The exploration extended into untargeted biomarker discovery via proteomic analysis, revealing several proteins with differential expression in PD patient serum samples. This analysis pointed to the potential involvement of proteins like NOTCH1, ALCAM, DUS3, CNTN4 and CD36 in the pathophysiology of PD. Building on the proteomic analysis, CNTN4, which has been reported to be expressed in the olfactory system, was investigated due to the known olfactory deficits in PD. It showed a decline in its plasma levels in PD patients and inversely correlated with both disease progression and CSF t-α-synuclein levels. However, its inconsistent olfactory bulb expression in PD, incidental Lewy Body Disease, and controls suggested a multifaceted role in PD pathology. This body of work underscores the critical role of multi-marker strategies in the accurate diagnosis and personalized management of PD.

Date of Award	2024
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences