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

There are currently limited molecular markers of Parkinson’s 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 Parkinson’s disease cohorts to identify novel protein biomarkers for these purposes, resulting in one of the largest such resources for Parkinson’s 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 Parkinson’s 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 Parkinson’s patients. We replicated and extended these findings in another undescribed proteomics cohort of de novo Parkinson’s disease participants from the Parkinson’s Progression Marker Initiative, where we found that AADC expression is upregulated in treatment naïve participants and is associated with motor and cognitive symptoms. We found that AADC expression can accurately distinguish Parkinson’s disease from healthy participants and Alzheimer’s 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 Parkinson’s disease with potential utility in multiple contexts. ### Competing Interest Statement J.R. and T.W-C. are founders and advisors of Teal Omics, where they have an equity stake. K.P. is on the Scientific Advisory Board for Curasen, where she receives consulting fees and stock options. K.P. is on the Scientific Advisory Board for Amprion, where she receives stock options. ### Funding Statement This research was supported by grants from the NIH (NS075097, KP; NS115114, KP; AG048076, AW; P50 AG047366 and P30 AG066515, VWH, KP, LT, TJM, and TWC; NS062684 TJM, LT, and KP), Michael J. Fox Foundation for Parkinson's disease Research (KP, TWC), Alzheimer's Association and McKnight Foundation (GK), The Knight Initiative for Brain Resilience (KP and TWC). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The IRB of Stanford University School of Medicine gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Individual level proteomics data from the present study will be made available upon reasonable request to the authors, contingent on approval for data access via the Stanford Alzheimer's Disease Research Center.