The diagnosis of dementia with Lewy bodies (DLB) is challenging, as this common neurological condition show significant overlap of clinical and pathological presentations with Alzheimer’s Disease (AD). Only a limited number of specific biomarkers have been widely analyzed for DLB, with previous studies on α-syn in cerebrospinal fluid (CSF) showing conflicting results. A study from Charlotte Teunissen’s group at Amsterdam University Medical Centers used eleven Olink® Target 96 protein panels to screen almost 1,000 proteins in CSF samples from a discovery cohort of patients with DLB (n = 109), AD (n = 235) and cognitively unimpaired controls (n = 190). Potential biomarkers that provided the highest performance discrimination between DLB and AD/controls were then used to develop a custom Olink® Focus panel for validation in independent cohorts.
In the discovery phase, 665 CSF proteins were included in the statistical analysis, identifying around 50 with significant nominal associations to DLB vs AD, many of which were enriched in myelination processes among others. The dopamine biosynthesis enzyme DDC was the strongest dysregulated protein, and could efficiently discriminate DLB from controls (AUC=0.91) and AD (AUC=0.81). Classification modeling then identified a 7-protein signature with superior performance to DDC alone (DDC, CRH, MMP-3, ABL1, MMP-10, THOP1 & FCER2) that could discriminate DLB vs AD with an AUC=0.93 and DLB vs controls with an AUC=0.95.
A custom panel using the same Olink Proximity Extension Assay (PEA) technology was then developed to measure six of the seven proteins (DDC, CRH, MMP-3, ABL1, MMP-10, THOP1) and this was validated in several independent cohorts, showing AUC>0.90 for discrimination of DLB vs AD and controls. Furthermore, in an exploratory study, some of the markers in the custom panel also showed associations with different specific measures of DLB pathophysiology. Finally, given some known molecular overlaps between DLB and Parkinson’s Disease (PD), the authors also referenced data from a separate study that used the Olink® Explore platform in a PD cohort. They saw that CSF markers within the panel related to DLB (DDC, FCER2, CRH and MMP3) were all significantly dysregulated or showed nominal significance in both the prodromal and symptomatic phase of PD compared to controls.
The authors concluded that the biomarkers identified are ready to be employed to define their added value and potential context of use in clinical settings and trials within the context of DLB. They also stated that the workflow employed in this study may ultimately facilitate bench-to-bedside translation of biofluid-based biomarker findings and could thus be also relevant for other research fields.
del Campo M, Vermunt L, Peeters CFW, et al. CSF proteome profiling reveals biomarkers to discriminate dementia with Lewy bodies from Alzheimer´s disease. (2023) Nature Communications, DOI: 10.1038/s41467-023-41122-y
We here employed a high-throughput proteomics method, PEA, that allows analysis of large cohorts, with the additional advantage that custom multiplex immunoassays including the markers of interest can be smoothly developed for large-scale validation
del Campo et al. (2023)
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