Relationship between striatal dopaminergic depletion and cognitive milestone in Parkinson's disease: A comprehensive analysis of striatal subregions, laterality, and nonlinear relationships

BackgroundIn Parkinson's disease (PD), striatal dopaminergic degeneration follows a posterior-anterior gradient, with asymmetric involvement and an exponential decline in early disease stages. Previous investigations of the relationship between striatal dopamine transporter (DAT) availability and cognitive impairment in PD have been insufficient, especially in longitudinal studies.ObjectiveTo examine the longitudinal associations between baseline DAT availability and cognitive milestone (CogM) from the perspectives of striatal subregions, laterality, and nonlinear threshold effects.MethodsA total of 467 patients with early, sporadic PD without CogM and with available striatal DAT data at baseline were included from the Parkinson's Progression Markers Initiative database. Annual follow-up data over eight years were analyzed. Standard multivariable Cox and restricted cubic spline (RCS) Cox models were used to assess the associations between DAT uptake and CogM. Two-piecewise Cox regression was used to explore potential threshold effects.ResultsThe 8-year cumulative probability of being CogM-free was 66.0%. In multivariable Cox models, DAT uptake in the ipsilateral, but not contralateral, caudate and putamen was inversely associated with CogM. RCS Cox models revealed a linear negative association for the ipsilateral caudate, but an L-shaped association for the ipsilateral putamen. Two-piecewise Cox regression identified a threshold effect at a DAT uptake of 1.04 in the ipsilateral putamen, below which the risk of CogM increased significantly.ConclusionsBaseline ipsilateral caudate DAT uptake shows a linear inverse relationship with CogM, highlighting its potential as an early predictive biomarker. The L-shaped association observed for ipsilateral putamen DAT warrants further mechanistic investigation.