Cholinergic Disruption Contributes to Motoric Cognitive Dysfunction in Cerebral Small Vessel Disease

Cognitive decline and gait disturbance are often observed simultaneously in patients with small vessel disease (SVD), also known as motoric cognitive dysfunction. However, it remains unknown whether cholinergic system disruption contributes to motoric cognitive dysfunction. In this cross-sectional, single-center study conducted in the Netherlands, we included 213 patients with SVD between 2020 and 2021, all of whom had multimodal magnetic resonance imaging scans, gait assessments using the 6-meter walk test, and cognitive test battery data available. Cholinergic cortical (through external capsule and cingulum) and thalamic projections (pedunculopontine nucleus to thalamus) were reconstructed using probabilistic tractography on diffusion images, followed by the quantification of the disruption in these tracts with diffusion metrics derived from neurite orientation dispersion and density imaging model. Conventional magnetic resonance imaging markers for SVD were assessed.Covariates, including neurite orientation dispersion and density imaging metrics in the white matter control mask and SVD markers, were adjusted in linear regression. A total of 213 patients with SVD were included, with a mean (SD) age of 74.6 (6.8) years, of whom 96 (45.1%) were women. Conventional SVD markers are differentially associated with disrupted cholinergic pathways, with white matter hyperintensities (WMH) being the main contributor (R² highest for neurite density index, 0.38). WMH within the external capsule cholinergic pathway is more strongly associated with the neurite orientation dispersion and density imaging metrics in this tract compared with total WMH volume or WMH outside cholinergic projections. In contrast, WMH within the cingulum pathway contributes less to neurite orientation dispersion and density imaging variability (R²=0.18-0.33 versus 0.22-0.38). Disruption in cholinergic cortical pathways was associated with concurrent decline in performance of cognition and gait (external capsule pathway cerebrospinal fluid isotropic volume fraction, β=-10.77; P=0.004; cingulum pathway cerebrospinal fluid isotropic volume fraction, β=-13.38; P=0.011), adjusted for the covariates. Taken together, our findings suggest that disruption in cholinergic cortical pathways attributable to SVD, rather than cholinergic thalamic pathways, contributes to the motoric cognitive dysfunction in patients with SVD.