白质病变破坏帕金森病中与认知相关的胆碱能通路

White matter lesions are associated with cognitive impairment in Parkinson’s disease, but the underlying neurobiological mechanisms remain unclear. One hypothesis is that strategically located white matter lesions disrupt long-range white matter pathways crucial for cognitive functioning, particularly cholinergic projections from the basal forebrain, contributing to cognitive decline. Using volumetric measures of basal forebrain nuclei (T1 MRI proxy for brain cholinergic projection nuclei), quantitative white matter lesion assessments (fluid-attenuated inversion recovery MRI) and a presynaptic cholinergic marker ( 18 F-FEOBV PET), we tested a mechanistic model of white matter lesion effects on basal forebrain cholinergic projections and nuclei, and how these disruptions relate to cognition.We analysed data from 127 mid-to-advanced-stage patients with Parkinson’s disease without dementia. Periventricular and deep white matter lesion burdens were quantified with the UBO Detector pipeline. Cognitive function was assessed across five domains using z -scores from a control group matched for age and education. Voxel-wise analyses examined associations between white matter lesion burden and cholinergic synaptic density, followed by mediation analyses testing whether cholinergic alterations mediated the relationship between white matter lesions and cognition, while correcting for sex, levodopa equivalent dose and disease duration.Voxel-wise analyses revealed that higher periventricular lesions burden was associated with reduced 18 F-FEOBV uptake in an insular–limbic–frontal–cingulum cluster, while deep lesions showed more topographically limited associations that disappeared after adjusting for periventricular burden. Periventricular lesions affected lateral and external Ch4 cholinergic projection pathways (81%–88% of patients), more frequently than deep white matter lesions (25%–47% of patients), except for the external capsule, which was equally affected by both.

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