RESUMO
OBJECTIVE: More than half of neurodegenerative disease patients have multiple pathologies at autopsy; however, most receive one diagnosis during life. We used the α-synuclein seed amplification assay (αSyn-SAA) and CSF biomarkers for amyloidosis and Alzheimer's disease (AD) neuropathological change (ADNC) to determine the frequency of co-pathologies in participants clinically diagnosed with Lewy body (LB) disease or AD. METHODS: Using receiver operating characteristic analyses on retrospective CSF samples from 150 participants determined αSyn-SAA accuracy, sensitivity, and specificity for identifying clinically defined LB disease and predicting future change in clinical diagnosis. CSF biomarkers helped determine the frequency of concomitant Lewy body pathology, ADNC, and/or amyloidosis in participants with LB disease and AD, across clinical spectra. RESULTS: Following a decade-long follow-up, the clinically or autopsy-defined diagnosis changed for nine participants. αSyn-SAA demonstrated improved accuracy (91.3%), sensitivity (89.3%), and specificity (93.3%) for identifying LB disease compared to all non-LB disease, highlighting the limitations of clinical diagnosis alone. When examining biomarkers of co-pathology, amyloidosis was present in 18%, 48%, and 71% (χ2 (2) = 13.56, p = 0.001) and AD biomarkers were present in 0%, 8.7%, and 42.9% (χ2 (2) = 18.44, p < 0.001) of LB disease participants with different stages of cognitive impairment respectively. Co-occurring biomarkers for αSyn-SAA and amyloidosis were present in 12% and 14% of AD compared to 43% and 57% LB disease participants with different stages of cognitive impairment (χ2 (3) = 13.87, p = 0.003). INTERPRETATION: Our study shows that using a combination of αSyn-SAA and AD biomarkers can identify people with αSyn, ADNC, and co-pathology better and earlier than traditional clinical diagnostic criteria alone.
RESUMO
Parkinson's disease (PD) starts at the molecular and cellular level long before motor symptoms appear, yet there are no early-stage molecular biomarkers for diagnosis, prognosis prediction, or monitoring therapeutic response. This lack of biomarkers greatly impedes patient care and translational research-L-DOPA remains the standard of care more than 50 years after its introduction. Here, we performed a large-scale, multi-tissue, and multi-platform proteomics study to identify new biomarkers for early diagnosis and disease monitoring in PD. We analyzed 4877 cerebrospinal fluid, blood plasma, and urine samples from participants across seven cohorts using three orthogonal proteomics methods: Olink proximity extension assay, SomaScan aptamer precipitation assay, and liquid chromatography-mass spectrometry proteomics. We discovered that hundreds of proteins were upregulated in the CSF, blood, or urine of PD patients, prodromal PD patients with DAT deficit and REM sleep behavior disorder or anosmia, and non-manifesting genetic carriers of LRRK2 and GBA mutations. We nominate multiple novel hits across our analyses as promising markers of early PD, including DOPA decarboxylase (DDC), also known as L-aromatic acid decarboxylase (AADC), sulfatase-modifying factor 1 (SUMF1), dipeptidyl peptidase 2/7 (DPP7), glutamyl aminopeptidase (ENPEP), WAP four-disulfide core domain 2 (WFDC2), and others. DDC, which catalyzes the final step in dopamine synthesis, particularly stands out as a novel hit with a compelling mechanistic link to PD pathogenesis. DDC is consistently upregulated in the CSF and urine of treatment-naïve PD, prodromal PD, and GBA or LRRK2 carrier participants by all three proteomics methods. We show that CSF DDC levels correlate with clinical symptom severity in treatment-naïve PD patients and can be used to accurately diagnose PD and prodromal PD. This suggests that urine and CSF DDC could be a promising diagnostic and prognostic marker with utility in both clinical care and translational research.
