Alpha-synuclein in cerebrospinal fluid

The current status of biochemical biomarker candidates for dementia with Lewy bodies (DLB) and synucleinopathy has been previously discussed. The majority of the studies on biochemical biomarkers were cross-sectional, retrospective, and tested with pathologically unproven subjects. α-Synuclein (A-syn) plays a pivotal role both in the development of the disease and propagation of the pathology in Parkinson’s disease (PD). Levels of total A-syn in cerebrospinal fluid (CSF) can discriminate PD from controls or tauopathies as groups. However, it is hard to diagnose an individual patient according to the level of CSF A-syn alone. The CSF total A-syn could also be useful as a surrogate biomarker for PD for monitoring the severity of the disease. CSF levels of A-syn oligomers could be a promising biomarker for the diagnosis of PD and are reported to correlate with motor and cognitive scores in PD, also suggesting their possible ability as a biomarker to monitor disease severity. With regard to the diagnosis of DLB, some studies, including two meta-analyses, demonstrated significantly lower CSF levels of total A-syn in DLB patients compared to AD patients. However, the sensitivity and specificity as well as diagnostic ability of CSF total A-syn remain to be elucidated. Whether CSF A-syn oligomers are useful or not for the diagnosis of DLB has not been examined. To study plasma levels of total and oligomeric A-syn, it is essential to eliminate the interference from heterophilic antibodies that have a significant impact on the assays of plasma A-syn, despite never being considered in any of the studies reported so far. For future studies developing biochemical biomarkers for DLB and synucleinopathy, it will be necessary to not only validate the already reported candidates and translate them to clinical practice but also to identify novel biomarkers that are more closely associated with the underlying pathophysiologies, including certain oligomers or protofibrils of A-syn that are specifically relevant to neurotoxicity and/or prion-like propagation of the diseases. To accomplish these goals, a large, prospective, and longitudinal cohort study carried out using standardized diagnostic criteria and stringent protocols with quality-controlled methods will definitely be needed.