CSF proteome profiling reveals highly specific biomarkers for dementia with Lewy bodies
CSF proteome profiling reveals highly specific biomarkers for dementia with Lewy bodies
ABSTRACT 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?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.
Irwin David J、Chen-Plotkin Alice、van Nee Mirrelijn、Vermunt Lisa、Hok-A-Hin Yanaika S.、Engelborghs Sebastiaan、Teunissen Charlotte E、van der Flier Wiesje M、Alcolea Daniel、Lemstra Afina W、Sieben Anne、Lle¨? Alberto、Peeters Carel FW、del Campo Marta
Department of Neurology, Perelman School of Medicine, University of PennsylvaniaDepartment of Neurology, Perelman School of Medicine, University of PennsylvaniaDepartment of Epidemiology & Data Science, Amsterdam Public Health research institute, Amsterdam University Medical Centers, Location VUmcNeurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam University Medical Centers, Location VUmc||Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam University Medical Centers, Location VUmcNeurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam University Medical Centers, Location VUmcReference Center for Biological Markers of Dementia (BIODEM), Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp||Vrije Universiteit Brussel, Center for Neurosciences (C4N), Neuroprotection and Neuromodulation Research Group (NEUR)||Universitair Ziekenhuis Brussel, Department of NeurologyNeurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam University Medical Centers, Location VUmcAlzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam University Medical Centers, Location VUmc||Mathematical & Statistical Methods group (Biometris), Wageningen University & ResearchDepartment of Neurology, Institut d?ˉInvestigacions Biom¨¨diques Sant Pau (IIB SANT PAU) - Hospital de Sant Pau, Universitat Aut¨°noma de Hospital de la Santa Creu i Sant Pau||Center of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED)Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam University Medical Centers, Location VUmcLab of neuropathology, Neurobiobank, Institute Born-Bunge, Antwerp UniversityDepartment of Neurology, Institut d?ˉInvestigacions Biom¨¨diques Sant Pau (IIB SANT PAU) - Hospital de Sant Pau, Universitat Aut¨°noma de Hospital de la Santa Creu i Sant Pau||Center of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED)Mathematical & Statistical Methods group (Biometris), Wageningen University & ResearchNeurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam University Medical Centers, Location VUmc||Barcelona?eta Brain Research Center, Pasqual Maragall Foundation||Departamento de Ciencias Farmac¨|uticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities
神经病学、精神病学生物科学研究方法、生物科学研究技术基础医学
Irwin David J,Chen-Plotkin Alice,van Nee Mirrelijn,Vermunt Lisa,Hok-A-Hin Yanaika S.,Engelborghs Sebastiaan,Teunissen Charlotte E,van der Flier Wiesje M,Alcolea Daniel,Lemstra Afina W,Sieben Anne,Lle¨? Alberto,Peeters Carel FW,del Campo Marta.CSF proteome profiling reveals highly specific biomarkers for dementia with Lewy bodies[EB/OL].(2025-03-28)[2025-05-16].https://www.medrxiv.org/content/10.1101/2023.07.10.23292447.点此复制
评论