Aromatic L-Amino Acid Decarboxylase is a novel fluid biomarker of Parkinson's disease

There are currently limited molecular markers of Parkinsons disease, and there is an urgent need for new markers to guide clinical care, support earlier diagnosis, and hasten drug development. Here, we performed CSF and plasma proteomics in 5 Parkinsons disease cohorts to identify novel protein biomarkers for these purposes, resulting in one of the largest such resources for Parkinsons disease to date. We discovered a consistent upregulation of the protein L-Aromatic Acid Decarboxylase (AADC, EC 4.1.1.28, DDC) in the CSF and plasma of Parkinsons disease patients. AADC is a key protein in the synthesis of dopamine and other monoamine neurotransmitters. We found that higher CSF AADC levels are associated with greater motor symptom severity in Parkinsons patients. We replicated and extended these findings in another undescribed proteomics cohort of de novo Parkinsons disease participants from the Parkinsons Progression Marker Initiative, where we found that AADC expression is upregulated in treatment naive participants and is associated with motor and cognitive symptoms. We found that AADC expression can accurately distinguish Parkinsons disease from healthy participants and Alzheimers disease participants in multiple independent cohorts, and developed a panel of 16 proteins that achieves 95% receiver operator area under the curve (ROC AUC) in distinguishing these three states. Our results suggest that CSF AADC is a marker of the underlying disease process in Parkinsons disease with potential utility in multiple contexts.