Subtype classification of Parkinson's disease based on cortical functional gradient heterogeneity and its neurotransmitter basis

Background Patients with Parkinson's disease (PD) exhibit significant differences in the manifestation patterns, severity, and progression rate of motor and non-motor symptoms, demonstrating a strong clinical heterogeneity, which poses a key challenge to the precision diagnosis and treatment. Purpose The present study aimed to investigate cortical functional gradients in PD patients, seek effective classification for PD patients, and further elucidate the potential neuromodulation basis of clinical heterogeneity. Materials and Method We engaged a cohort of 99 PD and 104 normal controls (NC). Our examination focused on cortical gradient alterations in both whole brain gradient and large-scale network gradient in PD. Then, we performed hierarchical clustering analysis on PD patients by using individual gradient heterogeneity. Finally, we employed postmortem gene expression of cortices to investigate the relationships between neuromodulation basis and cortical gradient alterations. Results PD displayed abnormal global gradient alterations with increase and decrease coexistence in different cortices. Diminished focal gradients were observed in both dorsal attention and ventral attention networks. Furthermore, we found that PD patients could be divided into neuropsychiatric PD (NPPD) and non-NPPD, with NPPD exhibiting cognitive impairment and emotional disorders. Moreover, we identified notably correlations between the gradient changes of PD and NPPD and the different gene expression. Conclusion These results provide a new framework for PD classification and offer significant theoretical foundations for elucidating the intricate interplay between macroscopic functional gradient changes and microscopic neuromodulation roles for PD and NPPD.