Strategic involvement of cholinergic pathways and executive dysfunction: Does location of white matter signal hyperintensities matter?

Cholinergic therapies have proven efficacious in the treatment of Alzheimer's disease, and recently in vascular and mixed dementia. We set out to evaluate the impact of putative cerebrovascular lesions involving cholinergic pathways in patients with cognitive impairment. White matter signal hyperintensities on magnetic resonance imaging involving cholinergic projections were classified according to a three-point rating scale for 171 individuals with cognitive impairment and 34 normal elderly controls. Medial temporal lobe width was measured, and a neuropsychological test battery was administered. Moderate or severe involvement of cholinergic pathways by white matter signal hyperintensities were identified in 60% of subjects with probable vascular dementia, 30% of subjects with possible/probable Alzheimer's disease, and 40% of subjects with cognitive impairment but no dementia. All control subjects were found to have minimal cholinergic pathway involvement. Medial temporal lobe width and signal hyperintensities on magnetic resonance imaging affecting cholinergic pathways were inversely related. Individuals with moderate and severe involvement of cholinergic pathways by white matter signal hyperintensities had greater impairment of executive function and visuospatial attention, despite equivalent degrees of global impairment and memory dysfunction when compared to those with minimal cholinergic pathway involvement. This is the first study to suggest that cerebrovascular disease may directly affect cholinergic projections and may exacerbate pre-existing cholinergic deficits of a degenerative nature, especially in probable Alzheimer's disease. Cerebrovascular compromise of cholinergic white matter projections may therefore be relevant in understanding the effects of cholinergic therapies.