Emergening molecular diagnostics tools for Alzheimer’s (AD) and other neurodegenerative diseases
1Clinical Biochemistry and Pharmacology, Odense University Hospital, University of Southern Denmark, Odense C, 2Clinical Biochemistry and Immunology, Statens Serum Institut, Copenhagen S, Denmark
Neurodegenerative diseases exert a considerable impact on the life of patients and their families and constitute a vast socioeconomic burden. Furthermore, these diseases are burdened by diagnostic challenges that delay precise and early diagnosis, give no insight into disease pathology and activity, and have limited usability for monitoring treatment effects. Putative new biomarkers should address all or some of these aspects. We here present new data on (1) specific post-translational protein modifications; and (2) specific post-transcriptional regulators (micro-RNAs, miRNAs) for improving biofluid-based diagnosis of neurodegenerative diseases. (1) The dissection of post-translational modifications (including phosphorylations, glycosylations, and oxidative modifications) of cerebrospinal fluid (CSF) proteins benefits from selective enrichment-LC-tandem mass spectrometry (MS/MS). We present a quantitative solid-phase assay for free cysteine-10 in transthyretin (TTR) prompted by the finding of increased oxidation of Cys-10-TTR in AD-CSF by immunoaffinity-LC-MS/MS in exploratory experiments. (2) The revelation of miRNAs as important regulators of protein expression combined with their presence in biofluids, the existence of organ-specific miRNAs, and the facility of their quantitation by standard molecular biology techniques makes extracellular miRNAs attractive as new analytes. Also, analysis of their targets shed light on regulatory pathways and the miRNAs themselves are amenable to inhibition of mimicking. The low concentration of miRNA, preanalytical issues, and lack of established normal ranges complicate studies of CSF-miRNAs. Nevertheless, we here present data on dysregulated miRNAs in AD-CSF compared with controls. As illustrated by our data future precision diagnostics of neurodegenerative diseases including a more comprehensive understanding of pathogenic mechanisms based on CSF or blood samples will likely benefit from the exploration of a combination of several different classes of biological molecules.
Keywords: Biomarker development, Brain, RNA