Thalamic volume links milder symptoms but faster dopaminergic decline in prodromal Parkinson disease

Background: Biological changes such as α-synuclein deposits and brain structural changes related to Parkinson’s disease (PD) may precede both clinical diagnosis and dopaminergic dysfunction. However,whether magnetic resonance imaging (MRI)-derived structural features are associated with clinical burden and can predict subsequent dopaminergic changes remains unclear. Purpose: To determine whether multilevel baseline MRI phenotypes are associated with concurrent clinical status (including motor severity, overall disease stage, and global cognitive performance) and longitudinal changes in the dopamine transporter (DAT) ratio, to localize the anatomical regions involved. Materials and Methods: In this longitudinal cohort study, we analysed T1-weighted MRI from 340 participants from the PPMI who were cerebrospinal fluid α-synuclein seed amplification assay (SAA)-positive, DAT-negative and without a clinical diagnosis of PD at baseline. Longitudinal mixed-effects models sequentially evaluated four broad MRI summary measures, seven prespecified regional measures and 25 thalamic nuclei. We assessed the link between MRI measures with motor severity, disease stage and cognition in the PPMI chohrt, and independently assessed in the Quebec Parkinson Network Neuroimaging Cohort. Results: None of the four broad MRI summary measures were associated with longitudinal changes in the DAT. Baseline thalamic volume was associated with an additional decrease in the annual DAT ratio of 0.018 (β = -0.018, 95% CI, [-0.031, -0.005]; F DR = 0.046). Nucleus-level analysis revealed five FDR-significant nuclei in the basal ganglia–thalamocortical loops. In the primary cohort, the five-nucleus composite was associated with lower Movement Disorder Society Unified Parkinson’s Disease Rating Scale Part III (UPDRS-III) scores (β = -0.790, F DR = 0.022). In the independent Quebec PD cohort, greater thalamic volume was associated with lower UPDRS-III scores (β = -4.382, F DR = 0.040), lower Hoehn–Yahr stages (OR = 0.320, F DR < 0.001) and higher Montreal Cognitive Assessment (MoCA) scores (β = 1.709, F DR = 0.002). Conclusion: Thalamic structure was selectively associated with subsequent decreases in the DAT among patients with broad baseline MRI phenotypes. Despite its association with faster subsequent DAT decline, the concurrent association of greater thalamic structure with milder clinical involvement indicates that the brain structure, current clinical state and subsequent dopaminergic dysfunction may not evolve synchronously during early PD.