A consequence of our progressively ageing global population is the increasing prevalence of worldwide age-related cognitive decline and dementia. In the absence of effective therapeutic interventions, identifying risk factors associated with cognitive decline becomes increasingly vital. Novel perspectives suggest that a dynamic bidirectional communication system between the gut, its microbiome, and the central nervous system, commonly referred to as the microbiota-gut-brain axis, may be a contributing factor for cognitive health and disease. However, the exact mechanisms remain undefined. Microbial-derived metabolites produced in the gut can cross the intestinal epithelial barrier, enter systemic circulation and trigger physiological responses both directly and indirectly affecting the central nervous system and its functions. Dysregulation of this system (i.e., dysbiosis) can modulate cytotoxic metabolite production, promote neuroinflammation and negatively impact cognition. In this review, we explore critical connections between microbial-derived metabolites (secondary bile acids, trimethylamine-N-oxide (TMAO), tryptophan derivatives and others) and their influence upon cognitive function and neurodegenerative disorders, with a particular interest in their less-explored role as risk factors of cognitive decline.

Recent findings challenge the prior notion that the cerebellum remains unaffected by Alzheimer's disease (AD). Yet, it is unclear whether AD exacerbates age-related cerebellar grey matter decline or engages distinct structural and functional territories. We performed a meta-analysis of cerebellar grey matter loss in normal ageing and AD. We mapped voxels with structural decline onto established brain networks, functional parcellations, and along gradients that govern the functional organisation of the cerebellum. Importantly, these gradients track continuous changes in cerebellar specialisation providing a more nuanced measure of the functional profile of regions vulnerable to ageing and AD. Gradient 1 progresses from motor to cognitive territories; Gradient 2 isolates attentional processing; Gradient 3 captures lateralisation differences in cognitive functions. We identified bilateral and right-lateralised posterior cerebellar atrophy in ageing and AD, respectively. Age- and AD-related structural decline only showed partial spatial overlap in right lobule VI/Crus I. Despite the seemingly distinct patterns of AD- and age-related atrophy, the functional profiles of these regions were similar. Both participate in the same macroscale networks (default mode, frontoparietal, attention), support executive functions and language processing, and did not exhibit a difference in relative positions along Gradients 1 or 2. However, Gradient 3 values were significantly different in ageing vs. AD, suggesting that the roles of left and right atrophied cerebellar regions exhibit subtle functional differences despite their membership in similar macroscale networks. These findings provide an unprecedented characterisation of structural and functional differences and similarities in cerebellar grey matter loss between normal ageing and AD.

A key component of disease prevention is the identification of at-risk individuals. Microbial dysbiosis in the early stages of cognitive decline and Alzheimer's disease (AD) and can modulate the levels of microbe-derived metabolites (MDM), thought to contribute to neuroinflammation, blood‒brain barrier dysfunction, and neuronal degeneration. However, the precise role of MDM in this process, as well as their potential value as risk factors, remains poorly understood. Mass spectrometry platforms determined the serum concentration of 33 metabolites (13 tryptophan-related compounds, 15 bile acid compounds, 3 TMAO-related metabolites and 2 cresol metabolites) from cognitively healthy subjects, subjective cognitive impairment (SCI) participants and mild cognitive impairment (MCI) participants (n = 50 per group, matched for age, BMI and sex). Multiple linear regression and machine learning techniques were applied to identify a metabolite panel capable of classifying early cognitive decline. 16S rRNA amplicon sequencing was employed to identify bacterial taxa associated with these metabolic changes. Multiple linear regression modelling, adjusted for sex, BMI, age, albumin (for its role in metabolite transport), liver and kidney function, and background diet, identified key neuroprotective metabolites, namely choline, 5-hydroxyindole acetic acid, and indole propionic acid (IPA), as lower in SCI and MCI individuals compared to healthy controls. In contrast, the cytotoxic metabolite, indoxyl sulfate, and kynurenic acid were elevated. A random forest algorithm with multiclass classification further validated these findings, highlighting six metabolites (indoxyl sulfate, choline, 5-hydroxyindole acetic acid, IPA, kynurenic acid, and kynurenine) as classifiers of early cognitive decline, achieving an area under the curve (AUC) of 0.79. These findings suggest that MDM may serve as putative composite biomarkers of early cognitive decline, offering potential clinical relevance for metabolic risk stratification and supporting the future development of minimally invasive screening tools.

Alzheimer's disease (AD) is projected to increase in prevalence, heightening the need for strategies to alleviate its neuropathological burden. The bioactive constituents of a Mediterranean-style diet are well-recognised for their neuroprotective properties. Due to their capacity to alter the gut microbiome composition, these benefits may involve modulation of the microbiota-gut-brain axis. In this study, we investigated whether a novel supplement enriched with key Mediterranean diet-derived bioactives (Neurosyn240) could reduce amyloid deposition and microglial activation in 5xFAD mice, a transgenic model of AD, through microbiota-mediated mechanisms. Male and female 5xFAD transgenic mice (n = 16 per sex) were randomly assigned to receive either a standard control diet or a diet supplemented with Neurosyn240 for 12 weeks. Employing a multi-omics approach, gut microbiota composition was profiled using 16S rRNA ampliconsequencing, serum metabolites were quantified via targeted metabolomics, and hippocampal gene expression was analysed through qPCR and RNA sequencing. Neuropathological markers, including amyloid-β deposition and microglial activation, were evaluated using immunofluorescence staining. Statistical analyses were performed using two-way ANOVA to examine the main effects of diet and sex and their interaction. Neurosyn240 significantly shifted the gut microbiome composition, which was associated with increased circulatory serotonin levels and decreased kynurenine and bile acids (TCA, HDCA, TDCA, CDCA and LCA) concentrations. In the brain, Neurosyn240 consumption led to a significant reduction in hippocampal amyloid deposits and Iba-1 positive microglia (p<0.05), which were associated with decreased LCA and increased serotonin, respectively. Hippocampal RNA sequencing further highlighted the upregulation of genes involved in promoting amyloid beta clearance mechanisms. Together, these findings highlight novel neuroprotective effects of Neurosyn240 in modulating metabolite-mediated pathways of the microbiota-gut-brain axis, accentuating its therapeutic potential against AD progression.

Introduction Psychological disorders including depression and anxiety are significant public health concerns. A Mediterranean-style dietary pattern (MDP) has been associated with improved mental well-being in observational studies. Evidence of the acute (defined as postprandial to 1 week) effects of an MDP on brain function, mood, cognition and important modulators, including sleep and the gut microbiota is limited. The current intervention aims to examine whether an MDP, compared with a Western diet (WD), improves mood, cognition and anxiety symptoms, postprandially, at 24-hour and after 5 days in adults with mild to moderate anxiety and depression. Methods and analysis Twenty-five UK adults (aged 18 or over) with mild to moderate anxiety and/or depression and low adherence to an MDP were recruited to a cross-over randomised controlled trial. Each participant undergoes a 5 day MDP and a 5 day WD in a randomised order with all meals provided. The co-primary outcomes are mood and anxiety, with secondary outcomes including cognitive function, brain perfusion (as assessed by MRI), sleep quality, blood pressure, plasma glucose, insulin, lipids, C-reactive protein, cortisol, brain-derived neurotrophic factor, gut microbiota speciation and microbial metabolites including short chain fatty acids. A linear mixed model and/or paired analysis will be used to compare the effects of treatments over time. Ethics and dissemination The study has received a favourable ethics opinion from the National Health Service London Queen Square Research Ethics Committee (22/LO/0796). The results will be disseminated through scientific journals and conferences. Trial registration number NCT05927376.

Background: many medications possess anticholinergic activity. Their use is associated with a number of serious adverse effects including cognitive effects. The cumulative anticholinergic effect of medications as assessed by tools such as the anticholinergic burden scale (AchB) can identify people particularly at risk of anticholinergic side-effects. Currently, >20 tools are available for clinicians to use, but there is no consensus on the most appropriate tool. Methods: a newly created online tool—International Anticholinergic Cognitive Burden Tool (IACT)—based on natural language processing and chemical structure analysis, was developed and made available for clinicians to test its functions. We carried out a survey (between 8th of February and 31st of March 2021) to assess the overall need for an assessment tool as well as the usability of the IACT. Results: a total of 110 responses were received from different countries and practitioners’ groups. The majority of the participants (86.11%) stated they would use a tool for AchB assessment if available and when they were asked to rate the IACT against other tools, amongst 34 responders, 20.59% rated it better and 8.82% rated it significantly better, 44.12% rated it neither better, nor worse, 14.71% rated it worse and 11.76% somewhat worse. Conclusion: there is a need for an anticholinergic burden calculator to assess the anticholinergicity of medications. Tools such as the IACT potentially could meet this demand due to its ability to assign scores to current and new medications appearing on the market based both on their chemical structure and reported adverse pharmacological effects.