Identification of novel cerebrospinal fluid biomarker candidates for dementia with Lewy bodies: a proteomic approach

Abstract

Background: 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. Here, we aimed to identify novel CSF biomarkers for DLB using a high-throughput proteomic approach. Methods: We 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. Results: In 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).

Pathologically Decreased CSF Levels of Synaptic Marker NPTX2 in DLB Are Correlated with Levels of Alpha-Synuclein and VGF

“…This is illustrated by their use in AD, where abnormal cerebral spinal fluid (CSF) level of Aβ 1–42, phosphorylated tau and total tau aid diagnosis [ 13 , 14 ] and can be used to outline the disease trajectory [ 13 ]. In a recent CSF proteomics study, we identified novel potential DLB biomarkers, including neuronal Pentraxin 2 (NPTX2), VGF (a non-acronym), and secretogranin II (SCGII) [ 15 ]. Interestingly, these markers are all related to synaptic functioning and synaptic vesicles.…”

Secreted Chaperones in Neurodegeneration

“…Seven independent proteomics studies have shown that the level of proSAAS in CSF taken from AD and/or FTD patients is reduced as compared to controls, suggesting possible cellular retention within the brain ( Davidsson et al, 2002 ; Abdi et al, 2006 ; Finehout et al, 2007 ; Jahn et al, 2011 ; Choi et al, 2013 ; Holtta et al, 2015 ; Spellman et al, 2015 ; reviewed in Pedrero-Prieto et al, 2020 ). Two very recent CSF studies support this reduction ( Rotunno et al, 2020 ; Van Steenoven et al, 2020 ).…”

Added value of cerebrospinal fluid multimarker analysis in diagnosis and progression of dementia

“…Other emerging CSF markers related to synaptic degeneration, such as GAP‐43, SNAP‐25, and NPTX‐2, have been also described to be highly sensitive and specific for AD [48–51]. Additionally, p‐tau‐217 has shown better correlation with amyloid brain load than p‐tau‐181 [52], and both tau isoforms have been reported to be present in early AD stages [53].…”