Nucleus basalis of Meynert revisited: anatomy, history and differential involvement in Alzheimer's and Parkinson's disease

Abstract

It has been well established that neuronal loss within the cholinergic nucleus basalis of Meynert (nbM) correlates with cognitive decline in dementing disorders such as Alzheimer's disease (AD). Friedrich Lewy first observed his eponymous inclusion bodies in the nbM of postmortem brain tissue from patients with Parkinson's disease (PD) and cell loss in this area can be at least as extensive as that seen in AD. There has been confusion with regard to the terminology and exact localisation of the nbM within the human basal forebrain for decades due to the diffuse and broad structure of this "nucleus". Also, while topographical projections from the nbM have been mapped out in subhuman primates, no direct clinicopathological correlations between subregional nbM and cortical pathology and specific cognitive profile decline have been performed in human tissue. Here, we review the evolution of the term nbM and the importance of standardised nbM sampling for neuropathological studies. Extensive review of the literature suggests that there is a caudorostral pattern of neuronal loss within the nbM in AD brains. However, the findings in PD are less clear due to the limited number of studies performed. Given the differing neuropsychiatric and cognitive deficits in Lewy body-associated dementias (PD dementia and dementia with Lewy bodies) as compared to AD, we hypothesise that a different pattern of neuronal loss will be found in the nbM of Lewy body disease brains. Understanding the functional significance of the subregions of the nbM could prove important in elucidating the pathogenesis of dementia in PD.

Fig. 1

A diagram of the human basal forebrain illustrating the location of the substantia innominata (as outlined). AC anterior commissure, Am amygdala, Cd caudate, GP globus pallidus, IC internal capsule, LV lateral ventricle, Pt putamen, SI substantia innominata

Fig. 2

Projected innervation map of the various Ch4 regions (Ch4a, green; Ch4i, blue; Ch4p, red) in the human brain on the lateral surface (top left) and at the mid-sagittal plane (top right). Cortical projection from the Ch4ai (turquoise) is currently unknown in the human brain. Topographical innervation in different subsectors of the nbM according to Mesulam et al. (bottom) [67, 69]

Fig. 3

Formalin-fixed, paraffin-embedded basal forebrain sections available from the Parkinson’s UK Tissue Bank at Imperial College, London, stained with H&E (a–c; g–i) and serial sections stained with choline acetyltransferase (ChAT) immunohistochemistry (Millipore AB144P, 1:100 with pressure cooker pretreatment in pH 6.0 citrate buffer) (d–f; j–l). Six subdivisions of the basal forebrain were defined and arranged rostrally (top left) to caudally (bottom right). a, d Level at nucleus accumbens. This level is defined by the absence of anterior commissure and the presence of a large caudate head with nucleus accumbens. b, e Pre-anterior nbM level. Anterior commissure appears in this section but it is located ventral to the globus pallidus and is rostral to decussation level. A large ventral striatum could be seen clearly with ChAT immunohistochemistry. c, f Most rostral anterior nbM level. This level is defined by the decussation of the anterior commissure. Ch4 neurons are defined by their location being lateral to the supraoptic nucleus and they are orientated at the medial–lateral axis parallel to the basal border of the section. g, j Most caudal anterior nbM level. The anterior commissure is split into two parts with medial end still decussating and lateral end located ventral to the globus pallidus. h, k Intermediate nbM level. At this level, the globus pallidus is split into the external and internal components by an inter-medullary lamina. The anterior commissure is located ventral to the putamen and sometimes the infundibulum could be seen. i, l Posterior nbM level. This is defined by the presence of mammillary body, small or absence of caudate and internal capsule occupying the medial half of the tissue. Asterisk denotes area of maximal density of ChAT-immunopositive cells in the nbM. Zoomed-in figure showing the ChAT-immunopositive neurons in the nbM at ×10 objectives. AC anterior commissure, Cd caudate, fx fornix, GP globus pallidus, GPe globus pallidus externa, GPi globus pallidus interna, ic internal capsule, inf infundibulum, mb mammillary body, nAcc nucleus accumbens, ot optic tract, Pt putamen, son supraoptic nucleus, VS ventral stratum

Fig. 4

Photographs showing the anatomical landmarks for the anterior, intermediate and posterior levels of the nucleus basalis of Meynert (nbM, as indicated by asterisk). At dissection, the first coronal slice is made through the mammillary body (MB), revealing the posterior nbM. Using a 0.5-cm cutting guide two further coronal slices will reveal the intermediate and anterior levels. These are specifically identified by the presence of discernible globus pallidus externa (GPe) and interna (GPi), and midline anterior commissure (AC), respectively. With normal anatomical variation between individuals, this general 0.5 cm interval may need slight modification, depending on brain size

Fig. 5

Projected schema of anatomical progression of pathology within the nbM with possible clinicopathological correlations. Hypothesised progression is indicated by dashed arrows