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

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.