Aims

Post-mortem work has shown local accumulation of amyloid-beta, p-tau in the nucleus basali of Meynert (NbM), which leads to cholinergic deficiency in Alzheimer’s disease (AD). In MRI, NbM volume loss and microstructural alterations have been reported in AD. We aim to investigate the effect of neuropathological hallmarks in the NbM on MRI-measured NbM volume and structural connectivity in AD.

Methods

Twenty AD and eleven age- and gender-matched non-neurological control donors underwent post-mortem in-situ 3T MRI: T1-w for NbM delineation and DTI (fractional anisotropy, FA, and mean diffusivity, MD) for quantifying the integrity of the NbM and the projections. NbM sections of 20 μm were immunohistochemically stained for ChAT, amyloid-beta, and p-tau, and analyzed with ImageJ for their area %-load. Group comparisons were assessed using non-parametric tests and MRI-pathology associations with linear mixed models.

Results

AD cases showed lower NbM volume (p=0.003) and higher MD (p=0.003), as well as higher amyloid-beta (p=0.003) and p-tau (p=0.004) load than controls. In addition, AD cases showed higher MD in frontal (p=0.017) and temporal (p=0.039) projections.

For MRI-pathology associations in combined groups, NbM atrophy associated with less ChAT load (r=0.58,p=0.005), and lower FA associated with higher amyloid-beta load (r=0.47,p=0.032) in the NbM. MD of parietal and temporal projections associated with NbM ChAT load (r=0.44,p=0.013;r=0.3,p=0.007), and FA of temporal projections (r=0.26,p=0.029) with NbM p-tau load.

Conclusions

Our results indicate that cholinergic degeneration due to AD pathology is not restricted to the NbM, but further impacts its projections to the cortex, which can be captured by diffusion MRI.