Abstract
BackgroundDiagnosis of dementia with Lewy bodies (DLB) is challenging, largely due to a lack of diagnostic tools. Cerebrospinal fluid (CSF) biomarkers have been proven useful in Alzheimer’s disease (AD) diagnosis. Here, we aimed to identify novel CSF biomarkers for DLB using a high-throughput proteomic approach.MethodsWe applied liquid chromatography/tandem mass spectrometry with label-free quantification to identify biomarker candidates to individual CSF samples from a well-characterized cohort comprising patients with DLB (n = 20) and controls (n = 20). Validation was performed using (1) the identical proteomic workflow in an independent cohort (n = 30), (2) proteomic data from patients with related neurodegenerative diseases (n = 149) and (3) orthogonal techniques in an extended cohort consisting of DLB patients and controls (n = 76). Additionally, we utilized random forest analysis to identify the subset of candidate markers that best distinguished DLB from all other groups.ResultsIn total, we identified 1995 proteins. In the discovery cohort, 69 proteins were differentially expressed in DLB compared to controls (p < 0.05). Independent cohort replication confirmed VGF, SCG2, NPTX2, NPTXR, PDYN and PCSK1N as candidate biomarkers for DLB. The downregulation of the candidate biomarkers was somewhat more pronounced in DLB in comparison with related neurodegenerative diseases. Using random forest analysis, we identified a panel of VGF, SCG2 and PDYN to best differentiate between DLB and other clinical groups (accuracy: 0.82 (95%CI: 0.75–0.89)). Moreover, we confirmed the decrease of VGF and NPTX2 in DLB by ELISA and SRM methods. Low CSF levels of all biomarker candidates, except PCSK1N, were associated with more pronounced cognitive decline (0.37 < r < 0.56, all p < 0.01).ConclusionWe identified and validated six novel CSF biomarkers for DLB. These biomarkers, particularly when used as a panel, show promise to improve diagnostic accuracy and strengthen the importance of synaptic dysfunction in the pathophysiology of DLB.
Highlights
Diagnosis of dementia with Lewy bodies (DLB) is challenging, largely due to a lack of diagnostic tools
Synaptic dysfunction and loss is evident in neurodegenerative diseases, our findings tentatively suggest that synaptic dysfunction appears to be more pronounced in DLB than in related neurodegenerative diseases, i.e. Alzheimer’s disease (AD), Parkinson’s disease (PD) and frontotemporal dementia (FTD), or may reflect differing synaptic deficits among neurodegenerative diseases
Our results might suggest that these candidate biomarkers, when used as a panel, show promise to improve diagnostic accuracy for DLB, which should be explored in future prospective validation studies
Summary
Diagnosis of dementia with Lewy bodies (DLB) is challenging, largely due to a lack of diagnostic tools. Cerebrospinal fluid (CSF) biomarkers have been proven useful in Alzheimer’s disease (AD) diagnosis. CSF biomarkers have been proven useful in AD, where a typical CSF profile of decreased levels of amyloid-β 1–42 (Aβ1–42) combined with increased levels of total and phosphorylated tau (t-tau, p-tau) protein levels supports the diagnosis of AD [6]. No such diagnostic biomarkers are available for DLB. CSF biomarkers for α-synuclein seem promising [7,8,9], but are still not sensitive and specific enough to function as single diagnostic biomarkers
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