Review: revisiting the human cholinergic nucleus of the diagonal band of Broca

Although the nucleus of the vertical limb of the diagonal band of Broca (nvlDBB) is the second largest cholinergic nucleus in the basal forebrain, after the nucleus basalis of Meynert (nbM), it has not generally been a focus for studies of neurodegenerative disorders. However, the nvlDBB does have an important projection to the hippocampus and discrete lesions of the rostral basal forebrain have been shown to disrupt retrieval memory function, a major deficit seen in patients with Lewy body disorders. One reason for its neglect is that the anatomical boundaries of the nvlDBB are ill defined and this area of the brain is not part of routine diagnostic sampling protocols. We have reviewed the history and anatomy of the nvlDBB and now propose guidelines for distinguishing nvlDBB from other neighbouring cholinergic cell groups for standardising future clinicopathological work. Thorough review of the literature regarding neurodegenerative conditions reveals inconsistent results in terms of cholinergic neuronal loss within the nvlDBB. This is likely to be due to the use of variable neuronal inclusion criteria and omission of cholinergic immunohistochemical markers. Extrapolating from those studies showing significant nvlDBB neuronal loss in Lewy body dementia, we propose an anatomical and functional connection between the cholinergic component of the nvlDBB (Ch2) and the CA2 subfield in the hippocampus which may be especially vulnerable in Lewy body disorders. This article is protected by copyright. All rights reserved

Differential expression of galanin in the cholinergic basal forebrain of patients with Lewy body disorders.

Depletion of cholinergic neurons within the nucleus basalis of Meynert (nbM) is thought to contribute to the development of cognitive impairments in both Alzheimers disease (AD) and Lewy body disorders (LBD). It has been reported that, in late stage AD, a network of fibres that contain the neuropeptide galanin displays significant hypertrophy and hyperinnervates the surviving cholinergic neurons. Galanin is considered as a highly inducible neuroprotective factor and in AD this is assumed to be part of a protective tissue response. The aim of this study was to determine if a similar galanin upregulation is present in the nbM in post-mortem tissue from patients with LBD. Gallatin immunohistochemistry was carried out on anterior nbM sections from 76 LBD cases (27 PD, 15 PD with mild cognitive impairment (MCI), 34 PD with dementia (PDD) and 4 aged-matched controls. Galaninergic innervation of cholinergic neurons was assessed on a semi-quantitative scale.The LBD group had significantly higher galaninergic innervation scores (p = 0.016) compared to controls. However, this difference was due to increased innervation density only in a subgroup of LBD cases and this correlated positively with choline acetyltransferase-immunopositive neuron density.Galanin upregulation within the basal forebrain cholinergic system in LBD, similar to that seen in AD, may represent an intrinsic adaptive response to neurodegeneration that is consistent with its proposed roles in neurogenesis and neuroprotection

Where is the human nucleus basalis of Meynert?

Poster Presentation: Ageing and NeurodegenerationIntroduction: The nucleus basalis of Meynert (nbM) is generally defined as the collection of cholinergic neurons located ventral to the anterior commissure. However, detailed anatomical studies on the basal forebrain of the rhesus monkey, using retrograde tracers and cholinergic markers, have revealed a number of different sub-regions that innervate the cortex topographically. It is not known whether this topography translates to the human brain directly and there is a lack of consistency between different studies with regards to the sub-regional anatomy within the human basal forebrain. Therefore, our aim was to simplify and standardise the anatomy of the basal forebrain with a focus on defining the sub-regions of the nbM based on the general consensus in the existing literature. Material and methods: Published literature which included description of the nbM subdivisions was reviewed and 222 basal forebrain sections were obtained from the Parkinson’s UK Tissue bank. Tissues were stained with H&E and immunohistochemistry with choline-acetyltransferase (ChAT) for the identification of cholinergic neurons. Key anatomical landmarks were noted and matched with stained tissue sections. Results: Based on the published literature and our own findings, the nbM can be divided into three clear divisions: the anterior nbM is defined by the level of anterior commissure decussation; Intermediate nbM by the splitting of globus pallidus and anterior commissure located ventral to the globus pallidus externa and putamen; and posterior nbM by the level of mammillary body and anterior commissure located ventral/ventrolateral to the putamen. Conclusion: We have established a simplified classification system of the human nbM. This should facilitate further research into clinico-pathological correlations between sub-regional nbM pathology and cognitive deficits found in different neurological disorders

Sub-regional nucleus basalis of Meynert pathology in Lewy body disorders

Oral Presentation: First scientific session – Neuropathology of Neurogeneration: no. O07This journal suppl. entitled: Special Issue: Proceedings of the 116th Meeting of the British Neuropathological Society, Institute of Child Health, London, UK, 4–6 March 2015INTRODUCTION: Cortical acetylcholine is essential for normal cognitive functioning and its innervation originates from the nucleus basalis of Meynert (nbM). Retrograde tracer studies on non-human primates have shown a topographic innervation from different sub-regions of the nbM with the anterior portion providing afferents to the frontal and medial cortical regions; intermediate nbM to the lateral cortical regions; and posterior division innervating the temporal polar region. In Alzheimer’s disease (AD), the posterior nbM has shown the greatest degree of neuronal loss. However, detailed sub-regional analysis of the nbM has not been performed on Lewy body disorders (LBD). With functional imaging studies highlighting the difference in cortical cholinergic deficits between AD and LBD, we hypothesise a differential susceptibility to pathology in LBD. MATERIAL AND METHODS: Basal forebrain tissues from 43 Parkinson’s disease (PD). 20 PD with mild cognitive impairment (PD-MCI), 61 PD with dementia (PDD), 8 Dementia with Lewy Bodies (DLB) and 9 age-matched controls were obtained from the Parkinson’s UK Tissue Bank. Tissues were stained with H&E for the determi- nation of nbM sub-regions, and immunohistochemistry, with choline acetyltransferase (ChAT) antibodies, for the quantification of cholinergic neurons. RESULTS: A graded decrease of ChAT-positive neuronal density was observed as PD cognitive disability increased. In PDD, all nbM sub-regions appeared to be equally affected, whereas the degree of neuronal loss in PD without cognitive deficit was most severe in the posterior nbM sub-region. No significant difference between sub-regional cell loss in PDD and DLB was observed. CONCLUSION: Our results show that sub-regional pathology exists in different LBD. Further work is now needed to determine if this corresponds to the findings from recent functional imaging studies.link_to_OA_fulltex

Differential pattern of neuronal loss in the cholinergic basal forebrain in Lewy body disorders

Session: 03a. Pathophysiology & Disease Mechanisms: cell to cell transmission and spreading of pathologyThis FREE journal suppl. entitled: Mechanisms, Clinical Strategies, and Promising Treatments of Neurodegenerative Diseases: 12th International Conference AD/PD™, Nice, March 2015Conference Theme: Mechanisms, Clinical Strategies, and Promising Treatments of Neurodegenerative DiseasesINTRODUCTION: The basal forebrain cholinergic system consists of the medial septum/diagonal band nucleus (MS/DBN), nucleus basalis of Meynert (nbM) and nucleus subputaminalis (NSP). These nuclei project to the hippocampus and various cortical regions. A posterior-anterior gradient of cortical cholinergic deficit in Lewy body disorders (LBD) has been reported on imaging studies. However, it is not clear whether this pattern is reflected by the neuronal loss in various basal forebrain cholinergic nuclei. OBJECTIVES: To characterise the pattern of neuronal loss in different subdivisions of the cholinergic basal forebrain in Lewy body disorders. METHODS: Tissue sections containing the basal forebrain from 93 PD, 100 PDD, 14 DLB and 15 age-matched controls were stained using immunohistochemistry with choline acetyltransferase (ChAT) antibodies. ChAT-positive neurons in the MS/DB, NSP and nbM were quantified, blind to the clinical diagnosis. Results: A significant reduction of ChAT-positive neurons was found in LBD cases, with demented cases showing a greater loss. All subdivisions of the nbM were equally affected in PDD whereas the anterior and posterior nbM have a greater loss in PD. DLB cases have a significantly lower number of ChAT-positive neurons in the MS/DBN. A trend of decrease in ChAT-positive neurons was observed in the NSP among LBD cases. CONCLUSIONS: We have identified a differential pattern of cell loss in various subdivisions of the cholinergic basal forebrain in LBD cases. This could possibly explain the specific cognitive profile presented by LBD patients and support findings from recent imaging studies.link_to_OA_fulltex

Bringing CLARITY to the human brain: visualization of Lewy pathology in three dimensions

Aims: CLARITY is a novel technique which enables three-dimensional visualisation of immunostained tissue for the study of circuitry and spatial interactions between cells and molecules in the brain. In this study we aimed to compare methodological differences in the application of CLARITY between rodent and large human post-mortem brain samples. In addition, we aimed to investigate if this technique could be used to visualise Lewy pathology in a post-mortem Parkinson’s brain. Methods: Rodent and human brain samples were clarified and immunostained using the passive version of the CLARITY technique. Samples were then immersed in different refractive index matching media before mounting and visualising under a confocal microscope. Results: We found that tissue clearing speed using passive CLARITY differs according to species (human vs rodents), brain region and degree of fixation (fresh vs formalin-fixed tissues). Furthermore, there were advantages to using specific refractive index matching media. We have applied this technique and have successfully visualised Lewy body inclusions in three dimensions within the nucleus basalis of Meynert, and the spatial relationship between monoaminergic fibres and Lewy pathologies among nigrostriatal fibres in the midbrain without the need for physical serial sectioning of brain tissue. Conclusions: The effective use of CLARITY on large samples of human tissue opens up many potential avenues for detailed pathological and morphological studies