Five-Year Longitudinal Trajectories of Non-Motor Symptoms in Relation to Baseline Dopaminergic Decline in Parkinson’s Disease

• Reduced baseline striatal DaT uptake is longitudinally associated with declines in working memory, executive function, verbal memory, and visuospatial ability, as well as increased anxiety, in Parkinson’s disease (PD) over a 5-year follow-up. • PD patients who developed depression 4–5 years post-baseline exhibited significantly lower baseline bilateral and contralateral caudate and striatum uptake. • The presence of Rapid eye movement behavioral disorder five years after baseline was linked to lower baseline bilateral and contralateral caudate, putamen, and striatum DaT uptake. • The DaT scan asymmetry index demonstrated modest diagnostic accuracy (AUC > 0.6) for differentiating between normal olfactory function or mild olfactory loss from complete smell impairment in PD. While Non-motor symptoms (NMS) in Parkinson’s disease (PD) substantially affect quality of life, their association with dopaminergic dysfunction remains unclear. This study examined longitudinal associations between NMS and striatal dopamine transporter single-photon emission computed tomography (DaT-SPECT) measures over five years in PD patients. We studied 258 PD patients from the Parkinson’s Progression Markers Initiative (PPMI). The associations between the baseline DaT-SPECT-derived specific binding ratios (SBR) in the caudate, putamen, and striatum and longitudinal NMS, including rapid eye movement sleep behavior disorder (RBD), Epworth Sleepiness Scale, impulsivity, depression, anxiety, cognition, and olfaction were investigated. Greater caudate SBR asymmetry at baseline was associated with poorer visuospatial reasoning at year 2 ( p < 0.001). Lower initial putamen and striatal SBR correlated with impaired verbal memory retention at year 3 ( p < 0.001). Reduced baseline bilateral putamen SBR were linked to deficits in working memory and executive function at year 4 ( p < 0.001). Decreased baseline putamen uptake was associated with higher anxiety five years after diagnosis ( p < 0.001). Lower baseline caudate and striatal uptake was noted in PD patients who manifested depression 4–5 years later, whereas diminished baseline caudate, putamen, and striatal SBR was detected in those who exhibited RBD five years post-diagnosis ( p < 0.05). Predictive modeling indicated modest diagnostic accuracy, with olfactory dysfunction best distinguished using the asymmetry index (AUC > 0.6). Reduced striatal dopamine uptake, particularly in the caudate and putamen, was associated with progression of NMS including anxiety, depression, memory loss, visuospatial impairment, and RBD. Baseline DaT-SPECT may serve as a useful tool for anticipating NMS trajectories in PD.