Basal forebrain septal nuclei are enlarged in healthy subjects prior to the development of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is known to be associated with loss of cholinergic neurons in the nucleus basalis of Meynert, located in the posterior basal forebrain. Structural changes of septal nuclei, located in the anterior basal forebrain, have not been well studied in AD. Using a validated algorithm, we manually traced septal nuclei on high-resolution coronal magnetic resonance imaging (MRI) in 40 subjects with mild cognitive impairment (MCI) or AD, 89 healthy controls, and 18 subjects who were cognitively normal at the time of MRI but went on to develop AD an average of 2.8 years later. We found that cognitively normal subjects destined to develop AD in the future had enlarged septal nuclei as compared to both healthy controls and patients with current MCI or AD. To our knowledge, this is the first time a brain structure has been found to be enlarged in association with risk of AD. Further research is needed to determine if septal enlargement reflects neuroplastic compensation, amyloid deposition, inflammation, or another process and to determine whether it can serve as an early MRI biomarker of AD.

Septal dysembryoplastic neuroepithelial tumor: a comprehensive clinical, imaging, histopathologic, and molecular analysis

“…The tumors were evaluated for location (involvement of the septal nuclei, septum pellucidum, fornices, subcallosal area, and anterior commissure), T1/T2/T2 fluid attenuated inversion recovery (FLAIR) signals, enhancement, and apparent diffusion coefficient (ADC) relative to the thalamus, calculated as ADC tumor / ADC thalamus . 10 The boundaries of the septum verum, which contains the Ch1 and Ch2 septal nuclei, were defined according to criteria reported by Butler et al 11 On MRI, these nuclei are delimited anteriorly by a line connecting the anterior margins of the globi pallidi, laterally by a vertical line extending inferiorly to the base of the brain from the inferomedial boundary of the lateral ventricle, superiorly by the membranous septum pellucidum, and posteriorly by the fornices.…”

Neuronal diversity and reciprocal connectivity between the vertebrate hippocampus and septum

“…Enlargement of the septal nuclei was also observed in Alzheimer's disease (AD) on magnetic resonance imaging (MRI) scans (Butler et al, 2018). Pronounced loss of the basal forebrain cholinergic cell groups has been the hallmark of AD pathology.…”

An update on magnetic resonance imaging markers in AD

“…The role of anterior basal forebrain structures in AD, in particular the septal region, has been less studied. A recent study 64 employed manual volumetric analysis of the septal nuclei in healthy subjects who developed MCI or AD. Healthy individuals converting to AD within an average of 2.8 years had enlarged septal nuclei as compared with the other groups.…”