Association of Striatal Dopamine Depletion and Brain Metabolism Changes With Motor and Cognitive Deficits in Patients With Parkinson Disease

Background and Objectives Parkinson disease (PD) shows degeneration of dopaminergic neurons in the substantia nigra and characteristic changes in brain metabolism. However, how they correlated and affect motor and cognitive dysfunction in PD has not yet been well elucidated. Methods In this single-site cross-sectional study, we enrolled patients with PD who underwent N-(3-[¹⁸F]fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl)nortropane (¹⁸F-FP-CIT) PET, ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET, the Movement Disorder Society–sponsored Unified PD Rating Scale examination, and detailed neuropsychological testing. General linear models and mediation analyses were implemented to investigate the association between striatal dopamine transporter availability, brain metabolism, and parkinsonian motor subscores or domain-specific cognitive scores. Healthy controls (HCs) who underwent ¹⁸F-FP-CIT and ¹⁸F-FDG PET were also enrolled. Results Compared with HCs (n = 38, mean age 67.3 ± 5.9 years; 19 women), patients with PD (n = 143, mean age 69.0 ± 9.0 years; 69 women) characteristically showed relative brain hypermetabolism and hypometabolism that correlated with striatal dopamine transporter availability. As the loss of putaminal dopamine transporter availability increased, brain metabolism relatively increased from the paracentral lobule, pons, and limbic system to the cerebellum and anterior cingulate cortex, whereas brain metabolism relatively decreased from the lateral temporal and frontal cortices to the occipital and inferior parietal cortices. Reduced putaminal dopamine was associated with a higher rigidity subscore by the mediation of relative hypermetabolism in the paracentral lobule (standardized indirect effect, β = −0.070, p = 0.025) and directly associated with a higher bradykinesia subscore (β = −0.274, p = 0.011). Reduced caudate dopamine was associated with a higher axial subscore (β = −0.125, p = 0.004) and lower executive (β = 0.229, p = 0.004), visuospatial (β = 0.139, p = 0.006), and memory (β = 0.140, p = 0.004) domain scores by the mediation of relative brain hypometabolism. The tremor subscore and language and attention scores were not associated with striatal dopamine availability or brain metabolism. Discussion Our findings suggest that in PD, striatal dopamine depletion and altered brain metabolism are closely linked, that changes in brain metabolism occur in specific spatial patterns depending on the degree of dopamine depletion, and that both differentially affect motor and cognitive dysfunction depending on each symptom.