Atrophy of the Cholinergic Basal Forebrain Over the Adult Age Range and in Early Stages of Alzheimer's Disease

Background: The basal forebrain cholinergic system (BFCS) is known to undergo moderate neurodegenerative changes during normal aging as well as severe atrophy in Alzheimer's disease (AD). However, there is a controversy regarding how the cholinergic lesion in AD relates to early and incipient stages of the disease. In vivo imaging studies on the structural integrity of the BFCS in normal and pathologic aging are rare. Methods: We applied automated morphometry techniques in combination with high-dimensional image warping and a cytoarchitectonic map of basal forebrain cholinergic nuclei to a large cross-sectional data set of high-resolution magnetic resonance imaging scans, covering the whole adult age range (20-94 years; n = 211) as well as patients with very mild AD (Clinical Dementia Rating = .5; n = 69) and clinically manifest AD (AD; Clinical Dementia Rating = 1; n = 28). For comparison, we investigated hippocampus volume using automated volumetry. Results: Volume of the BFCS declined from early adulthood on, and atrophy aggravated in advanced age. Volume reductions in very mild AD were most pronounced in posterior parts of the nucleus basalis of Meynert, whereas in AD, atrophy was more extensive and included the whole BFCS. In clinically manifest AD, the diagnostic accuracy of BFCS volume reached the diagnostic accuracy of hippocampus volume. Conclusions: Our findings indicate that cholinergic degeneration in AD occurs against a background of age-related atrophy and that exacerbated atrophy in AD can be detected at earliest stages of cognitive impairment. Automated in vivo morphometry of the BFCS may become a useful tool to assess BF cholinergic degeneration in normal and pathologic aging.