Altered Tryptophan-Kynurenine Pathway in Delirium: A Review of the Current Literature.

Delirium, a common form of acute brain dysfunction, is associated with increased morbidity and mortality, especially in older patients. The underlying pathophysiology of delirium is not clearly understood, but acute systemic inflammation is known to drive delirium in cases of acute illnesses, such as sepsis, trauma, and surgery. Based on psychomotor presentations, delirium has three main subtypes, such as hypoactive, hyperactive, and mixed subtype. There are similarities in the initial presentation of delirium with depression and dementia, especially in the hypoactive subtype. Hence, patients with hypoactive delirium are frequently misdiagnosed. The altered kynurenine pathway (KP) is a promising molecular pathway implicated in the pathogenesis of delirium. The KP is highly regulated in the immune system and influences neurological functions. The activation of indoleamine 2,3-dioxygenase, and specific KP neuroactive metabolites, such as quinolinic acid and kynurenic acid, could play a role in the event of delirium. Here, we collectively describe the roles of the KP and speculate on its relevance in delirium.

Lipopolysaccharide-Induced Delirium-like Behaviour in a Rat Model of Chronic Cerebral Hypoperfusion Is Associated with Increased Indoleamine 2,3-Dioxygenase Expression and Endotoxin Tolerance.

Indoleamine 2,3-dioxygenase (IDO) and the tryptophan-kynurenine pathway (TRP-KP) are upregulated in ageing and could be implicated in the pathogenesis of delirium. This study evaluated the role of IDO/KP in lipopolysaccharide (LPS)-induced delirium in an animal model of chronic cerebral hypoperfusion (CCH), a proposed model for delirium. CCH was induced by a permanent bilateral common carotid artery ligation (BCCAL) in Sprague Dawley rats to trigger chronic neuroinflammation-induced neurodegeneration. Eight weeks after permanent BCCAL, the rats were treated with a single systemic LPS. The rats were divided into three groups: (1) post-BCCAL rats treated with intraperitoneal (i.p.) saline, (2) post-BCCAL rats treated with i.p. LPS 100 µg/kg, and (3) sham-operated rats treated with i.p. LPS 100 µg/kg. Each group consisted of 10 male rats. To elucidate the LPS-induced delirium-like behaviour, natural and learned behaviour changes were assessed by a buried food test (BFT), open field test (OFT), and Y-maze test at 0, 24-, 48-, and 72 h after LPS treatment. Serum was collected after each session of behavioural assessment. The rats were euthanised after the last serum collection, and the hippocampi and cerebral cortex were collected. The TRP-KP neuroactive metabolites were measured in both serum and brain tissues using ELISA. Our data show that LPS treatment in CCH rats was associated with acute, transient, and fluctuated deficits in natural and learned behaviour, consistent with features of delirium. These behaviour deficits were mild compared to the sham-operated rats, which exhibited robust behaviour impairments. Additionally, heightened hippocampal IDO expression in the LPS-treated CCH rats was associated with reduced serum KP activity together with a decrease in the hippocampal quinolinic acid (QA) expression compared to the sham-operated rats, suggested for the presence of endotoxin tolerance through the immunomodulatory activity of IDO in the brain. These data provide new insight into the underlying mechanisms of delirium, and future studies should further explore the role of IDO modulation and its therapeutic potential in delirium.

ß-Hydroxybutyrate Regulates Activated Microglia to Alleviate Neurodegenerative Processes in Neurological Diseases: A Scoping Review.

This scoping review aimed to summarise the effects of the ketone body ß-hydroxybutyrate. The review details the revealed pathways and functional properties following its intervention in the context of neurodegenerative diseases. In this study, 5 research publications that met the inclusion and exclusion criteria were shortlisted. Following the intervention, we discovered a tendency of reduced inflammatory status in microglia, as evidenced by lower levels of pro-inflammatory mediators produced, reduced microgliosis in afflicted tissues, and enhanced cognitive functions in neurodegenerative models. We found that there is a significant overlap in the mechanism of action of ß-hydroxybutyrate (BHB) via activation of the G-protein-Coupled Receptor 109A (GPR109a) receptor and deactivation of the inflammasome complex. Furthermore, although comparing outcomes can be challenging due to the heterogeneity in the study model, the results we have assembled here were consistent, giving us confidence in the intervention's efficacy. We also discussed new studies where BHB is involved in various roles in regulating inflammation in microglia, allowing for fresh therapeutic targets against neurodegeneration. This brief review provides evidence to support the huge potential of BHB in the treatment of neurodegenerative illnesses.

Non-Invasive Prenatal Testing (NIPT): Reliability, Challenges, and Future Directions.

Non-invasive prenatal testing was first discovered in 1988; it was primarily thought to be able to detect common aneuploidies, such as Patau syndrome (T13), Edward Syndrome (T18), and Down syndrome (T21). It comprises a simple technique involving the analysis of cell-free foetal DNA (cffDNA) obtained through maternal serum, using advances in next-generation sequencing. NIPT has shown promise as a simple and low-risk screening test, leading various governments and private organizations worldwide to dedicate significant resources towards its integration into national healthcare initiatives as well as the formation of consortia and research studies aimed at standardizing its implementation. This article aims to review the reliability of NIPT while discussing the current challenges prevalent among different communities worldwide.

Regulatory role of the endocannabinoid system on glial cells toward cognitive function in Alzheimer's disease: A systematic review and meta-analysis of animal studies.

Objective: Over the last decade, researchers have sought to develop novel medications against dementia. One potential agent under investigation is cannabinoids. This review systematically appraised and meta-analyzed published pre-clinical research on the mechanism of endocannabinoid system modulation in glial cells and their effects on cognitive function in animal models of Alzheimer's disease (AD). Methods: A systematic review complying with PRISMA guidelines was conducted. Six databases were searched: EBSCOHost, Scopus, PubMed, CINAHL, Cochrane, and Web of Science, using the keywords AD, cannabinoid, glial cells, and cognition. The methodological quality of each selected pre-clinical study was evaluated using the SYRCLE risk of bias tool. A random-effects model was applied to analyze the data and calculate the effect size, while I2 and p-values were used to assess heterogeneity. Results: The analysis included 26 original articles describing (1050 rodents) with AD-like symptoms. Rodents treated with cannabinoid agonists showed significant reductions in escape latency (standard mean difference [SMD] = -1.26; 95% confidence interval [CI]: -1.77 to -0.76, p < 0.00001) and ability to discriminate novel objects (SMD = 1.40; 95% CI: 1.04 to 1.76, p < 0.00001) compared to the control group. Furthermore, a significant decrease in Aß plaques (SMD = -0.91; 95% CI: -1.55 to -0.27, p = 0.006) was observed in the endocannabinoid-treated group compared to the control group. Trends were observed toward neuroprotection, as represented by decreased levels of glial cell markers including glial fibrillary acid protein (SMD = -1.47; 95% CI: -2.56 to -0.38, p = 0.008) and Iba1 (SMD = -1.67; 95% CI: -2.56 to -0.79, p = 0.0002). Studies on the wild-type mice demonstrated significantly decreased levels of pro-inflammatory markers TNF-α, IL-1, and IL-6 (SMD = -2.28; 95% CI: -3.15 to -1.41, p = 0.00001). Despite the non-significant decrease in pro-inflammatory marker levels in transgenic mice (SMD = -0.47; 95% CI: -1.03 to 0.08, p = 0.09), the result favored the endocannabinoid-treated group over the control group. Conclusion: The revised data suggested that endocannabinoid stimulation promotes cognitive function via modulation of glial cells by decreasing pro-inflammatory markers in AD-like rodent models. Thus, cannabinoid agents may be required to modulate the downstream chain of effect to enhance cognitive stability against concurrent neuroinflammation in AD. Population-based studies and well-designed clinical trials are required to characterize the acceptability and real-world effectiveness of cannabinoid agents. Systematic Review Registration: [https://inplasy.com/inplasy-2022-8-0094/], identifier [Inplasy Protocol 3770].

Metabolomics Profiling of Age-Associated Metabolites in Malay Population.

Aging is a complex process characterized by progressive loss of functional abilities due to the accumulation of molecular damages. Metabolomics could offer novel insights into the predictors and mechanisms of aging. This cross-sectional study is aimed at identifying age-associated plasma metabolome in a Malay population. A total of 146 (90 females) healthy participants aged 28-69 were selected for the study. Untargeted metabolomics profiling was performed using liquid chromatography-tandem mass spectrometry. Association analysis was based on the general linear model. Gender-associated metabolites were adjusted for age, while age-associated metabolites were adjusted for gender or analyzed in a gender-stratified manner. Gender-associated metabolites such as 4-hydroxyphenyllactic acid, carnitine, cortisol, and testosterone sulfate showed higher levels in males than females. Deoxycholic acid and hippuric acid were among the metabolites with a positive association with age after being adjusted for gender, while 9(E),11(E)-conjugated linoleic acid, cortisol, and nicotinamide were negatively associated with age. In gender-stratified analysis, glutamine was one of the common metabolites that showed a direct association with age in both genders, while metabolites such as 11-deoxy prostaglandin F2ß, guanosine monophosphate, and testosterone sulfate were inversely associated with age in males and females. This study reveals several age-associated metabolites in Malays that could reflect the changes in metabolisms during aging and may be used to discern the risk of geriatric syndromes and disorders later. Further studies are required to determine the interplay between these metabolites and environmental factors on the functional outcomes during aging.

Application of Metabolomics in the Study of Starvation-Induced Autophagy in Saccharomyces cerevisiae: A Scoping Review.

This scoping review is aimed at the application of the metabolomics platform to dissect key metabolites and their intermediates to observe the regulatory mechanisms of starvation-induced autophagy in Saccharomyces cerevisiae. Four research papers were shortlisted in this review following the inclusion and exclusion criteria. We observed a commonly shared pathway undertaken by S. cerevisiae under nutritional stress. Targeted and untargeted metabolomics was applied in either of these studies using varying platforms resulting in the annotation of several different observable metabolites. We saw a commonly shared pathway undertaken by S. cerevisiae under nutritional stress. Following nitrogen starvation, the concentration of cellular nucleosides was altered as a result of autophagic RNA degradation. Additionally, it is also found that autophagy replenishes amino acid pools to sustain macromolecule synthesis. Furthermore, in glucose starvation, nucleosides were broken down into carbonaceous metabolites that are being funneled into the non-oxidative pentose phosphate pathway. The ribose salvage allows for the survival of starved yeast. Moreover, acute glucose starvation showed autophagy to be involved in maintaining ATP/energy levels. We highlighted the practicality of metabolomics as a tool to better understand the underlying mechanisms involved to maintain homeostasis by recycling degradative products to ensure the survival of S. cerevisiae under starvation. The application of metabolomics has extended the scope of autophagy and provided newer intervention targets against cancer as well as neurodegenerative diseases in which autophagy is implicated.

Studying the Relationship of Intermittent Fasting and ß-Amyloid in Animal Model of Alzheimer's Disease: A Scoping Review.

We examined the evidence for intermittent fasting (IF) as a preventative tool to influence ß-amyloid in animal models of Alzheimer's disease (AD). A Scopus, Ovid, PubMed, and Web of Science (WoS), search yielded 29 results using the keywords "amyloid beta", "intermittent fasting", "intermittent caloric restriction", "alternate day fasting", "modified alternate-day fasting", "time-restricted feeding", "Ramadan fast", "intermittent calori* restriction", "intermittent restrictive diet", and "Alzheimer*". Five research articles addressed directly the effects of intermittent fasting on ß-amyloid levels in animal models of AD: alternate day fasting (ADF) and time-restricted feeding (TRF) methods were incorporated in these studies. The study designs were found to be heterogeneous. Variations in the levels of ß-amyloid peptides or plaque in either the hippocampus, cortical areas, or both in animals following dietary intervention were observed as compared to the ad libitum group. Non-significant changes were observed in three studies, while two studies interestingly demonstrated amelioration and reduction in ß-amyloid levels. Given the conflicting results obtained from this study, significant care has to be taken into consideration before the protocol can be applied as a preventative approach to treat Alzheimer's disease. Longitudinal research is warranted to fully grasp how dietary habits can help alleviate the disease either through upstream or downstream of AD pathology.

Tocotrienol-Rich Fraction of Palm Oil Improves Behavioral Impairments and Regulates Metabolic Pathways in AßPP/PS1 Mice.

We have recently shown that the tocotrienol-rich fraction (TRF) of palm oil, a mixture of vitamin E analogs, improves amyloid pathology in vitro and in vivo. However, precise mechanisms remain unknown. In this study, we examined the effects of long-term (10 months) TRF treatment on behavioral impairments and brain metabolites in (15 months old) AßPP/PS1 double transgenic (Tg) Alzheimer's disease (AD) mice. The open field test, Morris water maze, and novel object recognition tasks revealed improved exploratory activity, spatial learning, and recognition memory, respectively, in TRF-treated Tg mice. Brain metabolite profiling of wild-type and Tg mice treated with and without TRF was performed using ultrahigh performance liquid chromatography (UHPLC) coupled to high-resolution accurate mass (HRAM)-orbitrap tandem mass spectrometry (MS/MS). Metabolic pathway analysis found perturbed metabolic pathways that linked to AD. TRF treatment partly ameliorated metabolic perturbations in Tg mouse hippocampus. The mechanism of this pre-emptive activity may occur via modulation of metabolic pathways dependent on Aß interaction or independent of Aß interaction.

Wide-ranging alterations in the brain fatty acid complement of subjects with late Alzheimer's disease as detected by GC-MS.

Disturbed lipid metabolism is a well-established feature of human Alzheimer's disease (AD). The present study used gas chromatography-mass spectrometry (GC-MS) analysis of fatty acid methyl esters (FAMES) to profile all detectable fatty acid (FA) species present in post-mortem neocortical tissue (Brodmann 7 region). Quantitative targeted analysis was undertaken from 29 subjects (n=15 age-matched controls; n=14 late-stage AD). GC-MS analysis of FAMES detected a total of 24 FAs and of these, 20 were fully quantifiable. The results showed significant and wide ranging elevations in AD brain FA concentrations. A total of 9 FAs were elevated in AD with cis-13,16-docosenoic acid increased most (170%; P=0.033). Intriguingly, docosahexanoic acid (DHA; C22:6) concentrations were elevated (47%; P=0.018) which conflicts with the findings of others (unaltered or decreased) in some brain regions after the onset of AD. Furthermore, our results appear to indicate that subject gender influences brain FA levels in AD subjects (but not in age-matched control subjects). Among AD subjects 7 FA species were significantly higher in males than in females. These preliminary findings pinpoint FA disturbances as potentially important in the pathology of AD. Further work is required to determine if such changes are influenced by disease severity or different types of dementia.