Cerebrospinal fluid biomarkers in human prion diseases

Cerebrospinal fluid (CSF) is the main component of the brain extracellular space and participates in the exchange of many biochemical products in the CNS. Consequently, CSF contains a dynamic and complex mixture of proteins that reflect the physiological or pathological state of the CNS. Changes in the CSF proteome have been described in various neurodegenerative disorders. These alterations are also thought to reflect pathological changes in the brain, and thus understanding them will contribute to a better awareness of the pathophysiology that underlies these disorders. Proteomics offers a new methodology for the ana-lysis of pathological changes and mechanisms occurring in neurodegenerative processes and provides the possibility of novel biomarker discovery in order to supplement faster, earlier and more precise diagnosis. In general, the following criteria have to be applied in order to qualify a protein or a gene as a potential biomarker: the selected parameters have to be sensitive (able to detect the abnormalities at early stage of disease), specific (to allow differential diagnosis), reproducible with a high positive predictive value, and should allow for disease monitoring as well as a potential therapeutic response. In Creutzfeldt-Jakob disease, two major approaches have been followed that aim to detect the pathological form of the prion protein (PrPSc) in various peripheral tissues, while other approaches look for surrogate parameters that are a consequence of the neurodegenerative process. While the amount of abnormal disease-related PrPSc in CSF and blood in human transmissible spongiform encephalopathies appears to be extremely low, the development of a PrPSc-based biomarker was hampered by technical problems and detection limits. However, a variety of other proteins have been investigated in the CSF, and recently a variety of potential biomarkers have been reported that contribute to clinical diagnosis. Already established markers are 14-3-3, beta-amyloid, tau-protein and phosphorylated isoforms, S100b, as well as neuron-specific enolase. Since some of these markers display certain limitations, the search continues. This review summarizes current knowledge of biomarker development in prion diseases and discusses perspectives for new approaches.