Biomarkers of neurodegenerative parkinsonisms: From current clinical to future biological definitions - literature review and our experience.

Over recent decades, the search for sensitive and specific biomarkers of degenerative parkinsonisms has intensified. So also has the number of clinical trials aimed at disease modification and the subsequent need for improved recruitment of participants in the earliest possible stages and with the highest diagnostic certainty. Also increasing in number have been searches for ways to determine target engagement and biological effect, along with tracking of disease progression or its modification. With post mortem neuropathological confirmation remaining the most definite diagnostic category for most conditions, the updated diagnostic criteria are slowly introducing some routine biomarkers as supportive tools, mostly related to symptoms such as loss of smell in Parkinson's Disease (PD) or demonstration of REM sleep behaviour disorders in both PD and multiple system atrophy (MSA), or structural or functional (chiefly dopaminergic) imaging, which sometimes lacks either sensitivity or specificity [specific MRI signs for MSA or progressive supranuclear palsy (PSP)]. However, potential new tools such as seed amplification assays (SAAs) and PET imaging of underlying alpha-synuclein and 4R-tau pathologies, while not without their own challenges, are being increasingly seen as the next generation of diagnostic tools. In this setting, proposals to biologically define these conditions, primarily for research purposes (which might eventually include clinical trials) are emerging. In this review, we aimed to overview of the current use of routine biomarkers and any future promise of biological definition by molecular markers tracking underlying pathology.