This PET and MRI study of 53 PD patients finds that asymmetry of striatal VMAT2 uptake and hippocampal CA2/3 subfield volumes are associated with cognitive impairment and interact to predict global cognition, especially in PD-MCI.

Provides candidate imaging biomarkers (striatal dopaminergic and hippocampal subfield asymmetry) that could aid stratification and endpoint selection for trials targeting cognitive decline in PD, though results are exploratory and sample-limited.

BACKGROUND: Striatal dopaminergic dysfunction and hippocampal degeneration contribute to cognitive impairment in Parkinson's disease (PD). However, their interaction in PD-related cognitive decline remains unclear. OBJECTIVE: We aimed to investigate whether asymmetry of striatal dopaminergic integrity and hippocampal subfield volume are associated with cognitive performance in PD, and whether their statistical interaction provides additional explanatory value. METHODS: A cohort of 53 participants from the Parkinson's Progression Markers Initiative (PPMI) was analyzed, including 33 PD with mild cognitive impairment (PD-MCI) patients and 20 PD with normal cognition (PD-NC) patients. All patients had complete 18F-AV-133 vesicular monoamine transporter 2 PET and 3D-T1w imaging. Asymmetry indices (AI) were calculated for striatal 18F-AV-133 standard uptake volume ratio (SUVR) and hippocampal subfield volumes. RESULTS: PD-MCI showed higher AI in caudate and anterior putamen uptake versus PD-NC. Hippocampal CA2/3 and granule cell layer AI correlated with MoCA. Caudate and anterior putamen uptake AI linked to multiple cognitive domains. Regression analysis revealed interactions between anterior putamen SUVR AI and CA2/3 AI on MoCA in PD (p = 0.039), and posterior putamen SUVR AI with CA2/3 AI on MoCA in PD-MCI (p = 0.002). CONCLUSION: Striatal dopaminergic asymmetry and hippocampal subfield asymmetry are both associated with cognitive impairment in PD. In exploratory regression models, the association between CA2/3 asymmetry and global cognition varied according to the degree of striatal dopaminergic asymmetry. These findings clarified the relationship between hippocampus and dopaminergic pathways in PD with cognitive decline, and deepen understanding of the pathophysiological mechanisms of cognitive impairment.