Multimodal imaging of >300 PD-spectrum participants reveals stage-dependent corticostriatal reorganization: early hyperconnectivity between the posterior caudate and primary motor cortex peaking around ~50% putaminal dopamine loss, and progressive loss of posterior putamen–posterior cortical…

Provides stage-specific functional circuit biomarkers that can inform disease staging and the timing/targets for circuit-level interventions (e.g., neuromodulation) despite limited direct molecular or druggable targets.

BACKGROUND AND OBJECTIVES: In Parkinson disease (PD), deafferentation of nigral dopaminergic neurons to the striatum leads to striatal dopamine depletion and impaired direct and indirect basal ganglia pathways, which in turn reduce thalamocortical excitation and ultimately lead to parkinsonism. Therefore, understanding the manifestation of motor deficits requires the evaluation of degree of striatal dopamine depletion and the related changes in striatal functional connectivity (FC) as the nigrostriatal system degenerates. METHODS: In this cross-sectional study, we recruited 326 patients with PD and 29 patients with idiopathic REM sleep behavior disorder who underwent brain resting-state functional MRI, N-(3-[18F]fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane PET, and the Unified Parkinson's Disease Rating Scale assessment. A total of 40 healthy controls (HCs) were recruited to determine the extent of striatal dopamine depletion in patients with PD spectrum, and another 40 HCs were recruited to compare corticostriatal FC with that of the patient group. Using a sliding window method, we examined changes in FC with seed regions in the anterior and posterior caudate and putamen on both the more affected and less affected sides as the mean putaminal dopamine declined from 70% to 20%. RESULTS: The more affected side of the posterior caudate showed elevated FC with the primary motor cortex and paracentral lobule, which was present before approximately 50% putaminal dopamine depletion, peaked around this depletion level, and disappeared when caudate dopamine was abnormally reduced. The more affected side of the posterior putamen showed reduced FC with the superior parietal cortex, precuneus, and cuneus when putaminal dopamine depletion reached approximately 50%, after which the motor symptoms deteriorated linearly. DISCUSSION: In summary, our study demonstrated that the FC between the posterior caudate and primary motor cortex was elevated from the prodromal to early stages of PD, a period in which motor symptom progression remained relatively slow. The FC between the posterior putamen and motor cortex remained unchanged, while its connectivity with the posterior cortical regions declined from the onset of motor symptoms, coinciding with the accelerated progression of motor deterioration. Collectively, our study demonstrated that corticostriatal connectivity undergoes functional reorganization across the different stages of PD, which is associated with motor symptoms.