Abstract

Cognitive deficits in Alzheimers disease, specifically amnestic (memory dominant) deficits, are associated with cholinergic degeneration in the basal forebrain. The cholinergic nucleus within the basal forebrain, the nucleus basalis of Meynert, exhibits local atrophy and reduced cortical tract integrity on MRI, and reveals amyloid-{beta} and phosphorylated-tau pathology at autopsy. To better understand the pathophysiology of nucleus basalis of Meynert atrophy and its neocortical projections in Alzheimers disease, we utilized a combined post-mortem in-situ MRI and histopathology approach. A total of 19 Alzheimers disease (10 amnestic and 9 non-amnestic) and 9 non-neurological control donors underwent 3T T1-weighted MRI for anatomical delineation and volume assessment of the nucleus basalis of Meynert, and diffusion-weighted imaging for microstructural assessment of the nucleus and its projections. At subsequent brain autopsy, tissue dissection and immunohistochemistry were performed for amyloid-{beta}, phosphorylated-tau and choline acetyltransferase. Compared to controls, we observed an MRI-derived volume reduction and altered microstructural integrity of the nucleus basalis of Meynert in Alzheimers disease donors. Furthermore, decreased cholinergic cell density was associated with reduced integrity of the nucleus and its tracts to the temporal lobe, specifically to the temporal pole of the superior temporal gyrus, and the parahippocampal gyrus. The association between cholinergic cell density and alteration to cortical tracts was specific for amnestic, compared to non-amnestic Alzheimers disease donors. Our study illustrates that the nucleus basalis of Meynert is severely affected in amnestic Alzheimers disease, both in terms of pathology within the nucleus, but also in terms of damage to its cortical projections, specifically to the temporal lobe, which may contribute to the observed cognitive deterioration.