From Mechanistic Insights to Rational Interventions in Parkinson’s Disease: An Integrated Approach with a Patient Perspective

Background/Objectives: Parkinson’s disease (PD) is characterized by the selective loss of nigrostriatal dopaminergic neurons, accompanied by the accumulation and spreading of misfolded α-synuclein aggregates. Proposed mechanisms relevant to PD include gut–brain propagation of pathology via autonomic circuits, autophagy-related maintenance of proteostasis, and sleep-associated glymphatic clearance of extracellular waste. These mechanisms have prompted interest in multimodal approaches targeting disease-relevant biological pathways. Whether such approaches modify the neurodegenerative process or predominantly promote functional adaptation and compensation remains an open question. Methods: In a real-world clinical setting, a single patient with early-stage PD was observed over two years while five interventions targeting disease-relevant pathways were introduced at different time points and partly overlapped. Evaluation included physician-based clinical assessments and patient-reported observations, complemented by wearable-derived monitoring of autonomic and sleep metrics during the final six months. Serial DAT-SPECT imaging at baseline and two-year follow-up assessed changes in DAT binding. Results: Motor impairment remained mild and the patient reported largely stable overall mobility, although the persistent unilateral tremor was perceived to increase gradually later in the observation period. During the final six months, wearable monitoring indicated relative stable nocturnal autonomic measures and no markedly atypical rapid eye movement (REM) sleep estimates, while suggesting reduced slow-wave sleep (SWS). Following implementation of a structured bedtime routine, wearable-derived SWS estimates increased. Serial DAT-SPECT imaging demonstrated lower striatal DAT binding at two-year follow-up despite clinical stability. Conclusions: In this individual case, relative clinical stability coexisted with a longitudinal reduction in striatal DAT binding. Although no inference regarding disease modification can be drawn from a single uncontrolled observation, this discordance illustrates the limitations of interpreting clinical stability alone as evidence of an unchanged underlying disease process.