Besides Alzheimer’s disease (AD), Dementia with Lewy Bodies (DLB) is the second most common form of progressive dementia, accounting for up to 20% of cases. The main protein component of Lewy Bodies, which form in the nerve cells of the brain, is ɑ-synuclein. Cerebrospinal fluid (CSF) has proven useful to aid the diagnosis of AD, however, reliable biomarkers in the fluid for other neurological diseases such as DLB have not yet been validated.
Charlotte E. Teunissen of the Neurochemistry Laboratory and Biobank at Vrije Universiteit Amsterdam, The Netherlands, and colleagues, aimed to discover new biomarker proteins in the CSF of DLB patients using a state-of-the-art mass spectrometry workflow followed by validation in other cohorts. The results were published in the journal Molecular Neurodegeneration.
In the initial DLB discovery cohort, 46 proteins were downregulated and 23 proteins were upregulated compared to matched control patients without Lewy Bodies. Proenkephalin-B (PDYN) and Periostin (POSTN) are examples of proteins decreased by more than 2 log2. HLA class II histocompatibility antigen DRB1-4 beta chain was upregulated 10-fold and Ubiquitin-conjugating enzyme E2 D2 (UBE2D2) was upregulated 6-fold.
In a second DLB replication cohort, Neurosecretory protein (VGF), Secretogranin-2 (SCG2), Neuronal pentraxin-2 (NPTX2), Neuronal pentraxin receptor (NPTXR), PDYN and ProSAAS (PCSK1N) expression changes were replicated. Notably, all of these replicated biomarkers were downregulated in CSF. VGF and NPTX2 downregulation in the CSF of DLB patients was confirmed by ELISA assay.
The validated DLB markers were then checked in AD, Parkinson’s Disease (PD) and frontotemporal dementia (FTD) cohorts and found to be comparable. Machine learning identified three DLB biomarker candidates in CSF that in combination are specific for DLB; VGF, SCG2 and PDYN.
A limitation of the study was that although the cohorts were relatively large for proteomics studies (up to 48 DLB patients in a cohort), it is relatively small for a machine learning study. Furthermore the training and “test” cohorts were identical in the present study, which is not ideal. Therefore the DLB marker panel requires further validation in larger cohorts.
“In conclusion, we identified and positively validated six novel proteins (VGF, SCG2, NPTX2, NPTXR, PDYN and PCSK1N) as promising biomarkers for DLB. Our results might suggest that these candidate biomarkers, particularly when used as a panel, show promise to improve diagnostic accuracy for DLB, which should be explored in future prospective validation studies,” concluded the authors.