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

Abstract

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 (rʹ = 0.46, P = 0.002) and pallidum (rʹ = 0.45, P = 0.002), and were negatively associated with inferior temporal (rʹ = −0.35, P = 0.002) and medial orbitofrontal (rʹ = −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.

Understanding brain function in vascular cognitive impairment and dementia with EEG and MEG: A systematic review

“…This type of deficit is a typical characteristic of AD, where it has been related to degenerative neuronal loss in the basal forebrain ( Sarter and Bruno, 2004 , Sarter and Bruno, 2002 , Sarter and Bruno, 1999 , Sarter and Bruno, 1997 ). However, a cholinergic deficit could also be caused by subcortical cerebrovascular damage to the cholinergic corticospinal pathways ( Lim et al, 2020 , Wang et al, 2009 ). Some studies have specifically shown that white matter hyperintensities could be related to the anatomical tracks of the cholinergic pathways ( Behl et al, 2007 , Shin et al, 2012 ).…”

Altered Neurovascular Coupling in Subcortical Ischemic Vascular Disease

“…The results echo the previous study. The parietal regions and medial temporal regions have been suggested to be related to visuospatial attention and working memory ( Wang et al, 2015 ; Lim et al, 2020 ). The lower scores in the Trial-Making Test and Stroop Test of SIVD patients in the present study may demonstrate that the abnormally decreased ReHo/CBF ratios in these brain regions were correlated with deficits in these specific cognitive domains.…”

Role of White Matter Hyperintensities and Related Risk Factors in Vascular Cognitive Impairment: A Review

“…These results raise the question of whether tau accumulation may be differentiated from its role in AD spectrum disorders in relation to WMHs and VCI. It is possible that accumulated tau contributes to VCI either by triggering continuous neurotoxic processes and vascular damage including WMHs, or by its local cumulative effects on the interruption of the cholinergic pathway [59] in combination with the microstructural alterations of WMHs [60]. Recent findings have shown that cells in the CNS can release extracellular vesicles (EVs), which are a series of tiny double-membrane structures (20-2000 nm) with membrane-related interaction regions [61], filled with different molecular materials (including proteins, lipids, DNA, and various RNA species).…”