Neuroimaging in advanced Parkinson's disease: insights into pathophysiology, biomarkers, and personalized therapies.

Advanced Parkinson's disease (APD) represents a late stage of Parkinson's disease and is characterized by complex motor and non-motor symptoms that are less responsive to oral dopaminergic therapies. While APD has a relevant impact on patients' quality of life and requires intensified treatment, consistent diagnostic criteria have only recently been proposed. The precise pathophysiology underlying the symptoms of APD remains poorly understood, making early prognostication and intervention difficult. Neuroimaging has emerged as a promising tool for elucidating the mechanisms driving APD, identifying biomarkers for disease staging, and predicting therapeutic response. Techniques such as molecular imaging and magnetic resonance imaging provide insight into molecular and structural changes associated with the progression of PD, including protein aggregation, neuroinflammation, and regional neurodegeneration. While positron emission tomography imaging of alpha-synuclein and other pathologies offers avenues for staging and differential diagnosis, advanced magnetic resonance imaging approaches have the potential for capturing subtle microstructural changes i.e. through neuromelanin-sensitive or diffusion-weighted imaging. However, the majority of imaging studies has focused on early Parkinson's disease, leaving their applicability to APD uncertain. Future research should prioritize the validation of neuroimaging findings in well-defined APD cohorts and extend their use to predict clinical milestones such as motor fluctuations, dyskinesia, and cognitive decline. These efforts are essential to advance personalized therapeutic strategies and bridge the gap between research and clinical management of APD.