Towards a Biologically Defined Diagnosis: Incorporating Pathophysiological Measures Into Parkinson's Disease Clinical Criteria.

Parkinson's disease is the second most common neurodegenerative disorder worldwide, as well as being the fastest-growing neurological disorder. Furthermore, PD corresponds to a significant burden on those diagnosed, their caregivers and healthcare systems, highlighting the critical need for early and accurate diagnosis. Effective diagnosis is essential not only for timely intervention but also for the development of disease-modifying treatments, which are currently unavailable for PD management. Historically, PD diagnosis and characterisation was heavily reliant on clinical presentation, which are only present after significant neurodegeneration has already occurred. Because of this, there is a consensus amongst the scientific community to transition away from clinical features and instead redefine PD diagnosis and staging based on biological presentation. This review discusses historical developments in clinical diagnostic criteria for PD as well as the role the recently developed frameworks such as SynNeurGe and the Neuronal alpha-Synuclein Disease-Integrated Staging System (NSD-ISS) will play in the further advancements of diagnostic practices. Furthermore, substantial research efforts into the pathobiology of PD have led to the development of novel in vivo assessments capable of detecting critical biomarkers of PD. Specialised imaging modalities, particularly nuclear imaging and magnetic resonance imaging, and biomarkers of α-synuclein pathology demonstrate high sensitivity and specificity for not only early diagnosis but also differential diagnosis between other parkinsonisms. Beyond diagnostic reforms, it is also important to identify markers that could serve as indicators of clinical course to aid in tailoring personalised treatment strategies. Therefore, this review also summarises key pathobiological hallmarks of PD beyond α-synuclein pathology, namely, dopaminergic denervation, copathologies and underlying indicators of neurodegeneration, such as iron deposition and neuroinflammation. Furthermore, strategies to assess such pathologies and their potential utility in the current paradigm shift towards biological characterisation are discussed.