CSF proteome profiling reveals highly specific biomarkers for dementia with Lewy bodies.

Diagnosis of dementia with Lewy bodies (DLB) is challenging and biofluid biomarkers specific for DLB are highly needed. Here we use proximity extension-based multiplex assays to establish the specific cerebrospinal fluid (CSF) proteomic changes that underlie DLB in an unprecedented well-characterized cohort of 109 DLB patients, 235 patients with Alzheime[r]s disease (AD) and 190 controls. We identified more than 50 CSF proteins dysregulated in DLB, which were especially related to myelination processes. An enzyme involved in dopamine biosynthesis (L-amino acid decarboxylase, DDC) was the strongest dysregulated protein in DLB (>1.5 fold-change vs.CON or AD; q<1E-16) and could discriminate DLB from controls and AD patients with high accuracy (AUC: 0.91 and 0.81 respectively). We modelled a CSF protein panel containing only seven of these markers, which discriminate DLB from AD with higher performance (AUC: 0.93, 95%CI: 0.86-0.98). We developed custom multiplex assays for six of these markers (DDC, CRH, MMP-3, ABL1, MMP-10 and THOP1); and validated their performance in independent cohorts (n=329; AUCs: 0.68-0.90), including an autopsy cohort (n=76; AUCs: 0.90-0.95). This extensive and unique DLB CSF proteome study depicts specific protein changes underlying DLB pathophysiology. It translates these findings into a custom CSF biomarker panel able to identify DLB patients with high accuracy in different independent cohorts, providing new testing opportunities for diagnostic settings and clinical trials.