Structural (dys)connectivity associates with cholinergic cell density of the nucleus basalis of Meynert in Alzheimer's disease

Cognitive deficits in Alzheimer's 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-β and phosphorylated-tau pathology at autopsy. To better understand the pathophysiology of nucleus basalis of Meynert atrophy and its neocortical projections in Alzheimer's disease, we utilized a combined post-mortem in-situ MRI and histopathology approach. A total of 19 Alzheimer's 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-β, 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 Alzheimer's 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 Alzheimer's disease donors. Our study illustrates that the nucleus basalis of Meynert is severely affected in amnestic Alzheimer's 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.

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Nucleus basalis neuronal loss and neuritic plaques in advanced Alzheimer's disease

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y86-052 ◽

1986 ◽

Vol 64 (3) ◽

pp. 318-324 ◽

Cited By ~ 12

Author(s):

Pierre Etienne ◽

Yves Robitaille ◽

Serge Gauthier ◽

N. P. V. Nair

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Basal Forebrain ◽

Neuronal Loss ◽

Cell Loss ◽

Nucleus Basalis ◽

Nucleus Basalis Of Meynert ◽

Neuritic Plaques ◽

Cholinergic Cell

All our advanced severe cases of Alzheimer's disease had dramatic cholinergic cell loss in the basal forebrain, even after correction for cell or nucleolus shrinkage. We examined the relation between cell loss in the various subdivisions of the nucleus basalis of Meynert and plaque counts in corresponding and noncorresponding projection areas. This relation was not interpretable because of the ambiguity in the data.

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Basal forebrain volume reliably predicts the cortical spread of Alzheimer’s degeneration

Brain ◽

10.1093/brain/awaa012 ◽

2020 ◽

Vol 143 (3) ◽

pp. 993-1009 ◽

Cited By ~ 2

Author(s):

Sara Fernández-Cabello ◽

Martin Kronbichler ◽

Koene R A Van Dijk ◽

James A Goodman ◽

R Nathan Spreng ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Basal Forebrain ◽

Grey Matter ◽

Amyloid Β ◽

Predictive Modelling ◽

Nucleus Basalis ◽

Seed Region ◽

Projection System

Abstract Alzheimer’s disease neurodegeneration is thought to spread across anatomically and functionally connected brain regions. However, the precise sequence of spread remains ambiguous. The prevailing model used to guide in vivo human neuroimaging and non-human animal research assumes that Alzheimer’s degeneration starts in the entorhinal cortices, before spreading to the temporoparietal cortex. Challenging this model, we previously provided evidence that in vivo markers of neurodegeneration within the nucleus basalis of Meynert (NbM), a subregion of the basal forebrain heavily populated by cortically projecting cholinergic neurons, precedes and predicts entorhinal degeneration. There have been few systematic attempts at directly comparing staging models using in vivo longitudinal biomarker data, and none to our knowledge testing if comparative evidence generalizes across independent samples. Here we addressed the sequence of pathological staging in Alzheimer’s disease using two independent samples of the Alzheimer’s Disease Neuroimaging Initiative (n1 = 284; n2 = 553) with harmonized CSF assays of amyloid-β and hyperphosphorylated tau (pTau), and longitudinal structural MRI data over 2 years. We derived measures of grey matter degeneration in a priori NbM and the entorhinal cortical regions of interest. To examine the spreading of degeneration, we used a predictive modelling strategy that tests whether baseline grey matter volume in a seed region accounts for longitudinal change in a target region. We demonstrated that predictive spread favoured the NbM→entorhinal over the entorhinal→NbM model. This evidence generalized across the independent samples. We also showed that CSF concentrations of pTau/amyloid-β moderated the observed predictive relationship, consistent with evidence in rodent models of an underlying trans-synaptic mechanism of pathophysiological spread. The moderating effect of CSF was robust to additional factors, including clinical diagnosis. We then applied our predictive modelling strategy to an exploratory whole-brain voxel-wise analysis to examine the spatial specificity of the NbM→entorhinal model. We found that smaller baseline NbM volumes predicted greater degeneration in localized regions of the entorhinal and perirhinal cortices. By contrast, smaller baseline entorhinal volumes predicted degeneration in the medial temporal cortex, recapitulating a prior influential staging model. Our findings suggest that degeneration of the basal forebrain cholinergic projection system is a robust and reliable upstream event of entorhinal and neocortical degeneration, calling into question a prevailing view of Alzheimer’s disease pathogenesis.

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Basal forebrain atrophy along the Alzheimer’s disease spectrum and its relevance for subjective cognitive decline

10.21203/rs.3.rs-20438/v1 ◽

2020 ◽

Author(s):

Shumei Li ◽

Michel J. Grothe ◽

Marcel Daamen ◽

Steffen Wolfsgruber ◽

Frederic Brosseron ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Cognitive Decline ◽

Basal Forebrain ◽

Nucleus Basalis ◽

Nucleus Basalis Of Meynert ◽

Subjective Cognitive Decline ◽

Healthy Controls ◽

Cholinergic Basal Forebrain

Abstract Background There is growing evidence in the literature that the cholinergic basal forebrain might be one of the earliest affected structures in Alzheimer’s disease (AD). Recent data suggest that individuals with preclinical Alzheimer’s pathology already show atrophy of the posterior nucleus basalis of Meynert and that this even precedes the atrophy of the entorhinal cortex. Here we investigated whether basal forebrain volume reductions might not only be detectable in the mild cognitive impairment (MCI) and dementia stage of AD, but also in subjective cognitive decline (SCD) individuals who represent an at-risk population for preclinical AD, and examine the relationship with cognitive performance and amyloid-beta pathology. Methods Basal forebrain volumes of 341 participants from the multi-center German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study, including 135 healthy controls, 110 SCD, 60 MCI, and 36 AD, were analyzed using high-resolution T1-weighted images. Healthy controls and SCD participants were further grouped into amyloid-positive and amyloid-negative cases according to their cerebrospinal fluid Aβ42/40 ratio. Associations between basal forebrain volume, neuropsychological performance, and amyloid load were evaluated. Results Apart from confirming progressive basal forebrain atrophy from MCI to AD, atrophy of the posterior of nucleus basalis of Meynert was also observed in subjective cognitive decline with confirmed evidence for preclinical Alzheimer’s pathology, based on the Aβ42/40 ratio. This atrophy was neither evident in subjects with SCD without amyloid pathology nor in healthy controls with amyloid pathology. Additionally, the volume of the posterior of nucleus basalis of Meynert was significantly correlated with amyloid Aβ42/40 ratio in SCD but not in healthy controls. Conclusion Our results confirm that basal forebrain atrophy occurs early along the Alzheimer’s disease trajectory. The observed volume reduction of the cholinergic basal forebrain in Aβ-positive participants with subjective cognitive complains and the absence of any volume reductions in the Aβ-positive healthy controls suggests that these ‘subjective cognitive decline’ symptoms reflect progression from stage 1 (asymptomatic) to stage 2 (transitional cognitive impairment) of the Alzheimer’s continuum (according to the recent National Institute on Aging-Alzheimer’s Association Research Framework), revealing the beginning neurodegeneration on a macroscopic level.

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Functional connectivity of the nucleus basalis of Meynert in Lewy body dementia and Alzheimer’s disease

International Psychogeriatrics ◽

10.1017/s1041610220003944 ◽

2021 ◽

pp. 1-6

Author(s):

Julia Schumacher ◽

Alan J. Thomas ◽

Luis R. Peraza ◽

Michael Firbank ◽

John T. O’Brien ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Functional Connectivity ◽

Lewy Body ◽

Cholinergic System ◽

Structural Changes ◽

Lewy Body Dementia ◽

Occipital Cortex ◽

Nucleus Basalis ◽

Nucleus Basalis Of Meynert

ABSTRACT Cholinergic deficits are a hallmark of Alzheimer’s disease (AD) and Lewy body dementia (LBD). The nucleus basalis of Meynert (NBM) provides the major source of cortical cholinergic input; studying its functional connectivity might, therefore, provide a tool for probing the cholinergic system and its degeneration in neurodegenerative diseases. Forty-six LBD patients, 29 AD patients, and 31 healthy age-matched controls underwent resting-state functional magnetic resonance imaging (fMRI). A seed-based analysis was applied with seeds in the left and right NBM to assess functional connectivity between the NBM and the rest of the brain. We found a shift from anticorrelation in controls to positive correlations in LBD between the right/left NBM and clusters in right/left occipital cortex. Our results indicate that there is an imbalance in functional connectivity between the NBM and primary visual areas in LBD, which provides new insights into alterations within a part of the corticopetal cholinergic system that go beyond structural changes.

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