Mild Cognitive Impairment in the Elderly is Associated with Volume Loss of the Cholinergic Basal Forebrain Region

Background Cholinergic neurons within the basal forebrain are assumed to be an early (preclinical) manifestation site of pathological changes in Alzheimer's disease (AD). Methods We used morphometric magnetic resonance imaging (MRI) to detect and quantify atrophic changes in the basal forebrain of subjects suffering from amnestic mild cognitive impairment (aMCI). Three Tesla magnetic resonance (MR) data of 26 aMCI patients, 46 cognitively normal elderly control subjects (CO), and 12 patients suffering from Alzheimer's dementia were analyzed, including segmentation and quantification of brain tissue as well as a segmentation of basal forebrain structures (substantia innominata [SI]). Results We found the volume of the SI to be significantly different between groups in that control subjects showed the largest SI volumes, followed by aMCI and AD patients. Conclusions These results are in line with the hypothesis that cell loss within the cholinergic basal forebrain regions occurs already in the early (predementia) stage of AD. In vivo quantification of these changes might be of use as a novel neuroimaging marker of cholinergic neurodegeneration in AD

Longitudinal Alzheimer\u27s Degeneration Reflects the Spatial Topography of Cholinergic Basal Forebrain Projections

© 2018 The Author(s) The cholinergic neurons of the basal forebrain (BF) provide virtually all of the brain\u27s cortical and amygdalar cholinergic input. They are particularly vulnerable to neuropathology in early Alzheimer\u27s disease (AD) and may trigger the emergence of neuropathology in their cortico-amygdalar projection system through cholinergic denervation and trans-synaptic spreading of misfolded proteins. We examined whether longitudinal degeneration within the BF can explain longitudinal cortico-amygdalar degeneration in older human adults with abnormal cerebrospinal fluid biomarkers of AD neuropathology. We focused on two BF subregions, which are known to innervate cortico-amygdalar regions via two distinct macroscopic cholinergic projections. To further assess whether structural degeneration of these regions in AD reflects cholinergic denervation, we used the [ 18 F] FEOBV radiotracer, which binds to cortico-amygdalar cholinergic terminals. We found that the two BF subregions explain spatially distinct patterns of cortico-amygdalar degeneration, which closely reflect their cholinergic projections, and overlap with [ 18 F] FEOBV indices of cholinergic denervation

Longitudinal basal forebrain degeneration interacts with TREM2/C3 biomarkers of inflammation in presymptomatic Alzheimer’s disease

Copyright © 2020 the authors Cholinergic inputs originating from the peripheral nervous system regulate the inflammatory immune responses of macrophages during clearance of blood-based pathogens. Because microglia are involved in clearing amyloid and tau pathology from the central nervous system, we hypothesized that cholinergic input originating from the basal forebrain might similarly regulate inflammatory immune responses to these pathologies in the aging brain. To explore this hypothesis, we leveraged the Alzheimer’s Disease Neuroimaging Initiative dataset. Cognitively normal older male and female human adults were differentiated according to the relative concentration of phosphorylated tau and amyloid in their cerebrospinal fluid, yielding neurotypical and preclinical, cognitively healthy, subgroups. We then tracked these two groups longitudinally with structural MRI and biomarkers of inflammation, including soluble sTREM2 levels in the CSF and complement C3 expression in the blood transcriptome. Longitudinal loss of basal forebrain volume was larger in the preclinical compared with the neurotypical subgroup. Across preclinical adults, loss of basal forebrain volume was associated with greater longitudinal accumulation of sTREM2 and higher peripheral blood C3 expression. None of these relationships were attributable to degeneration in the whole-brain gray matter volume. Preclinical APOE e4 carriers exhibited the largest loss of basal forebrain volume and highest C3 expression. Consistent with the known anti-inflammatory influence of the peripheral cholinergic pathways on macrophages, our findings indicate that a loss of central cholinergic input originating from the basal forebrain might remove a key check on microglial inflammation induced by amyloid and tau accumulation

Reduced monoaminergic nuclei MRI signal detectable in pre-symptomatic older adults with future memory decline

Evidence from murine models and human post-mortem studies indicates that monoaminergic nuclei undergo degeneration at the pre-symptomatic stage of Alzheimer’s disease (AD). Analysing 129 datasets from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and relying on the Clinical Dementia Rating as group-defining instrument, we hypothesised that the MRI signal of monoaminergic nuclei would be a statistically significant predictor of memory decline in participants initially recruited in ADNI as healthy adults. As opposed to a group of cognitively stable participants, participants developing memory decline had reduced signal in the ventral tegmental area at baseline, before any evidence of functional decline emerged. These findings indicate that monoaminergic degeneration predates the onset of memory decline in an AD-centred initiative, with a crucial involvement of very-early changes of a dopaminergic region. This translates into potential informative avenues for pharmacological treatment of pre-symptomatic AD

Clinicopathological investigations of the cholinergic basal forebrain in Lewy body disorders and ageing

Cholinergic dysfunction has long been associated with cognitive impairment in Alzheimer’s disease (AD). However, neuropathological and functional imaging studies have also found significant cortical cholinergic deficit in Lewy body disorders (LBD), but in a different pattern from that in AD. There is topographical cholinerigic innervation to the cortex and the hippocampus from the basal forebrain. In light of differences in cognitive deficits seen in LBD and AD, I hypothesised that cholinergic basal forebrain subregions are differentially affected in these disorders. In this thesis, novel tissue techniques have been developed for the visualisation of pathology in human post-mortem brain tissue in three-dimensions. Based on a thorough review of the literature and my personal observations, I have established a simplified subdivisional scheme of the nucleus basalis of Meynert (nbM) in the human brain. Using this scheme, a quantification of nbM cholinergic neurons and assessment of neuropathological burden were performed in a large cohort of LBD and AD cases. Severe neuronal depletion across the entire nbM was observed in LBD with cognitive impairment and relative sparing of the anterior nbM was found in AD, supporting findings from previous neuropathological and imaging studies. Further investigation was carried out in the more rostral, hippocampal-projecting cholinergic group in the vertical limb of the nucleus of the diagonal band of Broca. Significant neurodegeneration in this area was identified in LBD with cognitive impairment, but not AD, suggesting its possible role in retrieval memory function via projection to the hippocampal CA2 subfield. In the final section, it was demonstrated that lactacystin injection into the rat nbM can replicate certain pathological and clinical features of LBD with dementia and this may be a useful model for the disease. Results from these studies support my initial hypothesis regarding differential susceptibility of the basal forebrain subregions in LBD and AD.Open Acces

New Developments in Cholinergic Imaging in Alzheimer and Lewy Body Disorders

© 2020, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply. Purpose of Review: This paper aims to review novel trends in cholinergic neuroimaging in Alzheimer and Lewy body parkinsonian disorders. Recent Findings: The spectrum of cholinergic imaging is expanding with the availability of spatially more precise radioligands that allow assessment of previously less recognized subcortical and cortical structures with more dense cholinergic innervation. In addition, advances in MRI techniques now allow quantitative structural or functional assessment of both the cholinergic forebrain and the pedunculopontine nucleus, which may serve as non-invasive prognostic predictors. Multimodal imaging approaches, such as PET-MRI or multiligand PET, offer new insights into the dynamic and interactive roles of the cholinergic system at both local and larger-scale neural network levels. Summary: Our understanding of the heterogeneous roles of the cholinergic system in age-related diseases is evolving. Multimodal imaging approaches that provide complimentary views of the cholinergic system will be necessary to shed light on the impact of cholinergic degeneration on regional and large-scale neural networks that underpin clinical symptom manifestation in neurodegeneration