News about the Role of Fluid and Imaging Biomarkers in Neurodegenerative Diseases

Abstract

Biomarkers are molecules that are variable in their origin, nature, and mechanism of action; they are of great relevance in biology and also in medicine because of their specific connection with a single or several diseases. Biomarkers are of two types, which in some cases are operative with each other. Fluid biomarkers, started around 2000, are generated in fluid from specific proteins/peptides and miRNAs accumulated within two extracellular fluids, either the central spinal fluid or blood plasma. The switch of these proteins/peptides and miRNAs, from free to segregated within extracellular vesicles, has induced certain advantages including higher levels within fluids and lower operative expenses. Imaging biomarkers, started around 2004, are identified in vivo upon their binding by radiolabeled molecules subsequently revealed in the brain by positron emission tomography and/or other imaging techniques. A positive point for the latter approach is the quantitation of results, but expenses are much higher. At present, both types of biomarker are being extensively employed to study Alzheimer's and other neurodegenerative diseases, investigated from the presymptomatic to mature stages. In conclusion, biomarkers have revolutionized scientific and medical research and practice. Diagnosis, which is often inadequate when based on medical criteria only, has been recently improved by the multiplicity and specificity of biomarkers. Analogous results have been obtained for prognosis. In contrast, improvement of therapy has been limited or fully absent, especially for Alzheimer's in which progress has been inadequate. An urgent need at hand is therefore the progress of a new drug trial design together with patient management in clinical practice.

Keywords: Alzheimer’s and Parkinson’s diseases; PET; amyloid-β and tau; astrocytes; exosomes and ectosomes; extracellular vesicles; fluid and imaging biomarkers; miRNA; neurons; radiolabeled molecules; radiotracers.

Figure 1

Traffic of extracellular vesicles (EVs) released by a neural cell. The neural cell at the top (cytoplasm of grain color, marked 1) releases the two types of EVs, the small exosomes by exocytosis of multivesicular bodies (MVB), and the larger ectosomes by shedding of plasma membrane rafts. Upon release, the vesicles navigate in the extracellular fluid (light blue). Their targeting relevant for fluid biomarker generation can be accumulate either to the central spinal fluid (CSF) of the ventricular system (left, peach color, marked 2) or as shown by the arrows to the blood (right, red-pink color, marked 3). Additional CSF-to-blood EV transfer occurs by large vacuoles operative at the arachnoid villi (bottom, marked 4). Thus, molecules and EVs can move from the extracellular space and the CSF to the blood plasma. In the case of neurodegenerative diseases, the molecules and EVs of such origin account for significant fractions of the total transferred to the fluids.