Microstructural alterations of parafascicular nucleus pathways associated with freezing of gait in Parkinson's disease.
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The parafascicular nucleus (Pf) projects to the dorsal putamen (Dpu), subthalamic nucleus (STN) and nucleus accumbens (Nac), regions implicated in both motor and non-motor symptoms of Parkinson's disease. However, microstructural alterations of these pathways across different Parkinson's disease motor subtypes remain unclear and heterogeneity within the postural instability and gait disorder (PIGD) subtype, particularly with respect to the presence or absence of freezing of gait (FOG), has often been overlooked. Therefore, this study employed diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) to examine microstructural properties of Pf projections in patients with tremor-dominant Parkinson's disease (PDTD; n = 25), PIGD (n = 34) and healthy controls (HC; n = 38). PIGD patients were further divided into patients with FOG (PIGD-FOG; n = 21) and patients without FOG (PIGD-nFOG; n = 13), and microstructural metrics were comprehensively assessed and compared between the two subgroups. The discrimination effects of microstructural metrics in Pf pathways were detected using receiver operating characteristic (ROC) analyses, and the correlations between microstructural metrics and clinical features of Parkinson's disease were further analysed. Group comparisons revealed significant differences between the PIGD and HC groups, whereas no significant differences were observed between the PDTD and HC groups or between the PDTD and PIGD groups. Compared with HC, PIGD patients exhibited significant microstructural impairments in Pf-related pathways, with reduced fractional anisotropy (FA) and neurite density (NDI), along with increased axial diffusivity (AD), mean diffusivity (MD) and radial diffusivity (RD) (P < 0.05). Within the PIGD group, patients with FOG showed more severe degeneration of Pf pathways, particularly in the bilateral Pf-STN pathways. Specifically, FA and NDI values were reduced, while MD and RD values were increased in PIGD-FOG patients compared with PIGD-nFOG patients (P < 0.05). ROC analyses demonstrated that microstructural metrics in Pf pathways effectively discriminated PIGD-FOG from PIGD-nFOG patients. Moreover, microstructural impairments of Pf pathways were associated with more severe gait dysfunction, more advanced disease stage and poorer motor-related activities of daily living in PIGD patients and with greater FOG severity, cognitive impairment and worse motor-related activities of daily living in the PIGD-FOG subgroup. These findings indicate that microstructural alterations of Pf pathways are preferentially associated with the PIGD subtype and are more pronounced in patients with FOG. Together, these results underscore a strong association between Pf-related circuits and FOG in PIGD and highlight the importance of symptom-driven heterogeneity within motor subtypes.