Effect of cholinergic pathway disruption on cortical and subcortical volumes in subcortical vascular cognitive impairment

Background and purpose The brain's cholinergic network has various interconnections with the cortical and subcortical structures. Disruption of cholinergic pathways by white matter hyperintensities (WMH) may cause pathologic changes within brain regions. Thus, WMH may represent an important pathological contributor to subcortical vascular cognitive impairment (scVCI). We aimed to investigate associations between the magnitude of WMH and volumetric changes in cortical and subcortical regions innervated by cholinergic neurons in patients with scVCI. Methods We enrolled patients with scVCI, defined as moderate to severe WMH or multiple (>2) lacunar infarcts outside the brainstem. Cholinergic Pathway HyperIntensities Scale (CHIPS) scores were used to quantify the magnitude of cholinergic pathway disruptions by WMH. We measured cortical thickness and subcortical volumes of 11 brain regions innervated by cholinergic neurons. Partial correlation of brain region volumes with total CHIPS scores was obtained using multiple linear regression. Results In total, 80 patients were enrolled. The mean age was 78.4 +/- 6.5 years, median Mini-Mental State Examination score was 17 (interquartile range, 13-20) and median CHIPS score was 11 (interquartile range, 7-17). CHIPS scores were positively correlated with subcortical volumes of the putamen (rMODIFIER LETTER PRIME = 0.46, P = 0.002) and pallidum (rMODIFIER LETTER PRIME = 0.45, P = 0.002), and were negatively associated with inferior temporal (rMODIFIER LETTER PRIME = -0.35, P = 0.002) and medial orbitofrontal (rMODIFIER LETTER PRIME = -0.32, P = 0.002) cortical thickness. Conclusion Our study suggested that WMH in cholinergic pathways may contribute to volumetric structural changes in cortical and subcortical structures innervated by cholinergic neurons.