Limbic Structural Alterations and Structural Covariance Across Prodromal Phenotypes and Early Parkinson's Disease

ABSTRACT Background Non‐motor symptoms may precede motor diagnosis in Parkinson's disease (PD), but whether distinct prodromal phenotypes exhibit differential limbic structural alterations remains unclear. Purpose To investigate limbic structural alterations across prodromal PD phenotypes defined by rapid eye movement sleep behavior disorder (RBD) and/or hyposmia. Study Type Retrospective cross‐sectional study. Population/Subjects 315 age‐ and sex‐matched participants (mean age = 68.34 years; 233 men and 82 women): healthy controls (HC), prodromal RBD without hyposmia, hyposmia without RBD/dream‐enactment behavior, hyposmia with RBD/dream‐enactment behavior, and untreated PD ( n = 63/group). Field Strength/Sequence 3T sagittal T1‐weighted 3D MPRAGE or equivalent sequences; nominal slice thickness = 1.0 mm; in‐plane resolution = 1.0 × 1.0 mm; matrix = 256 × 256; FOV = 256 mm. Assessment Volumes of 34 limbic regions were extracted using FreeSurfer and ScLimbic, normalized to estimated total intracranial volume, and harmonized with ComBat. Statistical Tests One‐way ANCOVA, post hoc comparisons, trend analyses, rank‐based partial correlations, and structural covariance analyses. False discovery rate (FDR)‐adjusted p < 0.05 was considered significant. Results After FDR correction, significant group differences were mainly observed in the insula (left: 5.20 ± 1.74, 4.64 ± 1.77, 4.48 ± 1.50, 4.03 ± 1.30, 3.92 ± 2.14; right: 5.26 ± 1.74, 4.56 ± 2.00, 4.30 ± 1.47, 3.95 ± 1.43, 3.89 ± 2.36), orbitofrontal cortex (left: 9.46 ± 2.82, 8.48 ± 3.42, 7.63 ± 3.17, 7.38 ± 3.03, 6.63 ± 3.79; right: 9.37 ± 2.89, 8.51 ± 3.33, 7.85 ± 3.05, 7.16 ± 2.74, 6.97 ± 3.89), and left parahippocampal gyrus (1.56 ± 0.77, 1.56 ± 0.72, 1.29 ± 0.70, 1.10 ± 0.59, 0.97 ± 1.03). Across exploratory phenotype orderings, the strongest negative linear trends were observed in the orbitofrontal cortex (left: β = −0.319 and −0.287; right: β = −0.297 and −0.266), and left parahippocampal gyrus ( β = −0.297 and −0.268). Within‐group covariance maps revealed phenotype‐specific significant covariance patterns involving olfactory‐related and Papez circuit regions after FDR correction. Data Conclusion Limbic structural alterations differed across prodromal phenotypes. Hyposmia‐related phenotypes showed more extensive involvement of olfactory‐related and Papez circuit brain regions than RBD, while structural covariance patterns suggest phenotype‐specific differences in limbic structures. Evidence Level 3. Technical Efficacy Stage 2.