Structural (dys)connectivity associates with cholinergic cell density in Alzheimer's disease

Area of Science:

• Neuroscience
• Neuropathology
• Neuroimaging

Background:

• Cognitive deficits in Alzheimer's disease (AD) are linked to cholinergic system degeneration.
• The nucleus basalis of Meynert (NBM) in the basal forebrain is central to this cholinergic system.
• NBM atrophy and altered tract integrity are observed in AD.

Purpose of the Study:

• To investigate the pathophysiology of NBM atrophy and its neocortical projections in AD.
• To correlate in situ MRI findings with histopathology in AD brains.

Main Methods:

• Combined post-mortem in situ MRI (T1-weighted and diffusion-weighted imaging) and histopathology.
• Analysis of NBM volume, microstructural integrity, and cholinergic cell density.
• Immunohistochemistry for amyloid-β, phosphorylated-tau, and choline acetyltransferase.

Main Results:

• AD donors showed reduced NBM volume and altered microstructural integrity compared to controls.
• Decreased cholinergic cell density correlated with reduced integrity of NBM tracts to the temporal lobe (temporal pole, parahippocampal gyrus).
• Cholinergic cell density was specifically associated with cortical tract alterations in amnestic AD.

Conclusions:

• Cholinergic degeneration in the NBM contributes to damaged cortical projections in AD.
• This damage, particularly to temporal lobe connections, may underlie cognitive decline.
• Findings highlight the role of the NBM-cortical pathway in AD pathophysiology.