BACKGROUND: Subjective cognitive decline (SCD) is a risk factor for future cognitive impairment and dementia. It is uncertain whether the neurodegeneration of the cholinergic system is already present in SCD individuals. We aimed to review the current evidence about the association between SCD and biomarkers of degeneration in the cholinergic system. METHOD: Original articles were extracted from three databases: Pubmed, Web of Sciences, and Scopus, in January 2023. Two researchers screened the studies independently. RESULTS: A total of 11 research articles were selected. SCD was mostly based on amnestic cognitive complaints. Cholinergic system biomarkers included neuroimaging markers of basal forebrain volume, functional connectivity, transcranial magnetic stimulation, or biofluid. The evidence showed associations between basal forebrain atrophy, poorer connectivity of the cholinergic system, and SCD CONCLUSIONS: Degenerative changes in the cholinergic system can be present in SCD. Subjective complaints may help when identifying individuals with brain changes that are associated with cognitive impairment. These findings may have important implications in targeting individuals that may benefit from cholinergic-target treatments at very early stages of neurodegenerative diseases.
- MeSH
- Alzheimer Disease * MeSH
- Biomarkers MeSH
- Cholinergic Agents MeSH
- Cognitive Dysfunction * diagnostic imaging MeSH
- Humans MeSH
- Magnetic Resonance Imaging MeSH
- Neuroimaging methods MeSH
- Basal Forebrain * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- Systematic Review MeSH
BACKGROUND: Cholinergic deficit and medial temporal lobe (MTL) atrophy are hallmarks of Alzheimer's disease (AD) leading to early allocentric spatial navigation (aSN) impairment. APOEɛ4 allele (E4) is a major genetic risk factor for late-onset AD and contributes to cholinergic dysfunction. Basal forebrain (BF) nuclei, the major source of acetylcholine, project into multiple brain regions and, along with MTL and prefrontal cortex (PFC), are involved in aSN processing. OBJECTIVE: We aimed to determine different contributions of individual BF nuclei atrophy to aSN in E4 positive and E4 negative older adults without dementia and assess whether they operate on aSN through MTL and PFC or independently from these structures. METHODS: 120 participants (60 E4 positive, 60 E4 negative) from the Czech Brain Aging Study underwent structural MRI and aSN testing in real-space arena setting. Hippocampal and BF nuclei volumes and entorhinal cortex and PFC thickness were obtained. Associations between brain regions involved in aSN were assessed using MANOVA and complex model of mutual relationships was built using structural equation modelling (SEM). RESULTS: Path analysis based on SEM modeling revealed that BF Ch1-2, Ch4p, and Ch4ai nuclei volumes were indirectly associated with aSN performance through MTL (pch1 - 2 = 0.039; pch4p = 0.042) and PFC (pch4ai = 0.044). In the E4 negative group, aSN was indirectly associated with Ch1-2 nuclei volumes (p = 0.015), while in the E4 positive group, there was indirect effect of Ch4p nucleus (p = 0.035). CONCLUSION: Our findings suggest that in older adults without dementia, BF nuclei affect aSN processing indirectly, through MTL and PFC, and that APOE E4 moderates these associations.
- MeSH
- Alleles MeSH
- Alzheimer Disease * diagnostic imaging genetics MeSH
- Atrophy MeSH
- Cholinergic Agents MeSH
- Humans MeSH
- Magnetic Resonance Imaging MeSH
- Basal Forebrain * diagnostic imaging MeSH
- Aged MeSH
- Check Tag
- Humans MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Disruptions in social behaviour are prevalent in many neuropsychiatric disorders such as schizophrenia, bipolar disorder and autism spectrum disorders. However, the underlying neurochemical regulation of social behaviour is still not well understood. The central cholinergic system has been proposed to contribute to the regulation of social behaviour. For instance, decreased global levels of acetylcholine release in the brain leads to decreased social interaction and an impairment of social memory in mice. Nonetheless, it has been difficult to ascertain the specific brain areas where cholinergic signalling influences social preference and social memory. In this study, we investigated the impact of different forebrain cholinergic regions on social behaviour by examining mouse lines that differ in their regional expression level of the vesicular acetylcholine transporter-the protein that regulates acetylcholine secretion. We found that when cholinergic signalling is highly disrupted in the striatum, hippocampus, cortex and amygdala mice have intact social preference but are impaired in social memory, as they cannot remember a familiar conspecific nor recognize a novel one. A similar pattern emerges when acetylcholine release is disrupted mainly in the striatum, cortex, and amygdala; however, the ability to recognize novel conspecifics is retained. In contrast, cholinergic signalling of the striatum and amygdala does not appear to significantly contribute to the modulation of social memory and social preference. Furthermore, we demonstrated that increasing global cholinergic tone does not increase social behaviours. Together, these data suggest that cholinergic transmission from the hippocampus and cortex are important for regulating social memory.
The integrity of the cholinergic system plays a central role in cognitive decline both in normal aging and neurological disorders including Alzheimer's disease and vascular cognitive impairment. Most of the previous neuroimaging research has focused on the integrity of the cholinergic basal forebrain, or its sub-region the nucleus basalis of Meynert (NBM). Tractography using diffusion tensor imaging data may enable modelling of the NBM white matter projections. We investigated the contribution of NBM volume, NBM white matter projections, small vessel disease (SVD), and age to performance in attention and memory in 262 cognitively normal individuals (39-77 years of age, 53% female). We developed a multimodal MRI pipeline for NBM segmentation and diffusion-based tracking of NBM white matter projections, and computed white matter hypointensities (WM-hypo) as a marker of SVD. We successfully tracked pathways that closely resemble the spatial layout of the cholinergic system as seen in previous post-mortem and DTI tractography studies. We found that high WM-hypo load was associated with older age, male sex, and lower performance in attention and memory. A high WM-hypo load was also associated with lower integrity of the cholinergic system above and beyond the effect of age. In a multivariate model, age and integrity of NBM white matter projections were stronger contributors than WM-hypo load and NBM volume to performance in attention and memory. We conclude that the integrity of NBM white matter projections plays a fundamental role in cognitive aging. This and other modern neuroimaging methods offer new opportunities to re-evaluate the cholinergic hypothesis of cognitive aging.
- MeSH
- White Matter anatomy & histology diagnostic imaging MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Neural Pathways anatomy & histology diagnostic imaging MeSH
- Basal Nucleus of Meynert anatomy & histology diagnostic imaging MeSH
- Memory physiology MeSH
- Basal Forebrain anatomy & histology diagnostic imaging MeSH
- Attention physiology MeSH
- Aged MeSH
- Sex Factors MeSH
- Aging physiology MeSH
- Age Factors MeSH
- Diffusion Tensor Imaging * MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Hippocampal and basal forebrain (BF) atrophy is associated with allocentric navigation impairment in Alzheimer's disease (AD) and may lead to recruitment of compensatory navigation strategies. We examined navigation strategy preference, its association with allocentric navigation, and the role of hippocampal and BF volumes in this association in early clinical stages of AD. Sixty nine participants-amnestic mild cognitive impairment (aMCI) due to AD (n = 28), AD dementia (n = 21), and cognitively normal (CN) older adults (n = 20)-underwent virtual Y-maze strategy assessment, real-space navigation testing, cognitive assessment, and hippocampal and BF volumetry. Preference for egocentric over allocentric strategy increased with AD severity (aMCI: 67% vs. 33%; dementia: 94% vs. 6%), which contrasted with preference in the CN group (39% vs. 61%). Those with aMCI who preferred egocentric strategy had worse allocentric navigation. Among those with aMCI, hippocampal and BF atrophy explained up to 25% of the association between strategy preference and allocentric navigation. The preference for egocentric strategy in AD may reflect recruitment of compensatory extrahippocampal navigation strategies as adaptation to hippocampal and BF neurodegeneration.
- MeSH
- Alzheimer Disease pathology psychology MeSH
- Atrophy MeSH
- Maze Learning MeSH
- Nerve Degeneration MeSH
- Hippocampus pathology physiopathology MeSH
- Cognitive Dysfunction pathology psychology MeSH
- Middle Aged MeSH
- Humans MeSH
- Neuropsychological Tests MeSH
- Basal Forebrain pathology physiopathology MeSH
- Spatial Navigation physiology MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Severity of Illness Index MeSH
- Organ Size MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
There is a growing body of evidence that stressful events may affect the brain not only as a whole, but also in multiple laterality aspects. The present review is aimed at discussing the effect of stress and stress hormones on structural brain asymmetry. Differences and crossroads of functional and structural asymmetry are briefly mentioned throughout the document. The first part of this review summarizes major findings in the field of structural brain asymmetries in animals and humans from the evolutionary perspective. Additionally, effect of stress on animals is discussed generally. The second part then explores asymmetrical effects of stress on structural changes of principal brain areas - amygdala, hippocampus, neocortex, diencephalon, basal forebrain and basal ganglia from the point of normal lateralization, steroids, trauma and genetic factors. At the end we present hypothesis why stress appears to have asymmetrical effects on lateralized brain structures.
- MeSH
- Amygdala diagnostic imaging metabolism MeSH
- Basal Ganglia diagnostic imaging metabolism MeSH
- Biological Evolution MeSH
- Diencephalon diagnostic imaging metabolism MeSH
- Functional Laterality MeSH
- Glucocorticoids metabolism MeSH
- Hippocampus diagnostic imaging metabolism MeSH
- Humans MeSH
- Magnetic Resonance Imaging MeSH
- Brain diagnostic imaging metabolism MeSH
- Neocortex diagnostic imaging metabolism MeSH
- Basal Forebrain diagnostic imaging metabolism MeSH
- Stress Disorders, Post-Traumatic diagnostic imaging MeSH
- Stress, Psychological metabolism MeSH
- Pituitary-Adrenal System metabolism MeSH
- Hypothalamo-Hypophyseal System metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
