Search Results (106)

Background: Secondary (nosocomial) bacterial meningitis remains a serious problem in patients with severe brain damage. The aim of this study was to assess the differences in the aromatic metabolites of tryptophan, phenylalanine, and tyrosine, in serum and cerebrospinal fluid (CSF) samples collected simultaneously from patients with long-term sequelae of severe brain damage with suspected secondary bacterial meningitis. Methods: Group I included 16 paired serum and CSF samples from patients (N = 11) without secondary bacterial meningitis; group II included 13 paired serum and CSF samples from patients (N = 4) with secondary bacterial meningitis. Results: The median concentrations of serum 5-hydroxyindole-3-acetic, CSF 4-hydroxyphenyllactic (p-HPhLA), CSF 4-hydroxyphenylacetic, CSF phenyllactic, and indole-3-lactic acids in serum and CSF were statistically higher in group II compared to group I (p-value ≤ 0.03), while 4-hydroxyphenylpropionic and indole-3-acetic in serum were lower in group II compared to group I (p-value = 0.04). In group I, p-HPhLA serum concentrations were greater than or equal to its CSF concentrations in 14 paired samples; in group II, p-HPhLA concentrations in serum were lower than in CSF in all paired samples. Conclusions: The obtained results demonstrate the differences in the profile of aromatic metabolites in serum and CSF and may confirm the hypothesis of the p-HPhLA microbial origin in the CSF of patients with secondary bacterial meningitis. Full article

Memory impairment, ranging from mild memory impairment to neurodegenerative diseases such as Alzheimer’s disease, poses an escalating global health challenge that necessitates multi-targeted interventions to prevent progression. Health functional foods (HFFs), which include bioactive dietary compounds that not only provide basic nutrition but also function beyond that to modulate physiological pathways, offer a promising non-pharmacological strategy to preserve memory function. This review presents an integrative framework for the discovery, evaluation, and clinical translation of biomarkers responsive to HFFs in the context of preventing memory impairment. We examine both established clinical biomarkers, such as amyloid-β and tau in the cerebrospinal fluid, neuroimaging indicators, and memory assessments, as well as emerging nutritionally sensitive markers including cytokines, microRNAs, gut microbiota signatures, epigenetic modifications, and neuroactive metabolites. By leveraging systems biology approaches, we explore how network pharmacology, gut–brain axis modulation, and multi-omics integration can help to elucidate the complex interactions between HFF components and memory-related pathways such as neuroinflammation, oxidative stress, synaptic plasticity, and metabolic regulation. The review also addresses the translational pipeline for HFFs, from formulation and standardization to regulatory frameworks and clinical development, with an emphasis on precision nutrition strategies and cross-disciplinary integration. Ultimately, we propose a paradigm shift in memory health interventions, positioning HFFs as scientifically validated compounds for personalized nutrition within a preventative memory function framework. Full article

Background: Alzheimer’s disease is a neurodegenerative disease of unknown etiology. Employing a combination of techniques such as imaging modalities, cognitive tests and medical history evaluations is considered to be a reliable approach in diagnosing the disease. A characteristic feature of Alzheimer’s disease is the gradual atrophy of the hippocampus, which is also seen with aging but at a faster rate in individuals suffering from the disease. The trigger responsible for the atrophy remains unknown. Methods: In this study, patients were assessed using MRI brain imaging, blood and cerebrospinal fluid analysis. Results: The findings indicate that the levels of erythrocytes in the cerebrospinal fluid have a statistically significant longitudinal predictive marker effect on hippocampal atrophy. Mean arterial pressure showed modest statistical significance in hippocampal volume only in the Alzheimer’s disease group. Conclusions: The results of the study point to the significance of cerebrospinal fluid homeostasis in terms of elements capable of causing hippocampal atrophy under chronic conditions. Monitoring of the presence of erythrocytes in cerebrospinal fluid and their related metabolites may be of clinical significance in the long-term management of Alzheimer’s disease. Full article

Background: Intervertebral disc degeneration (IVDD) is caused by an imbalance between the catabolic and anabolic processes within intervertebral disc tissue. Several studies have suggested a potential association between cerebrospinal fluid metabolites (CFMs) and the development of IVDD. However, the existing evidence on the relationship between CFM and IVDD is limited and inconsistent. Methods: The data on 338 cerebrospinal fluid metabolites and intervertebral disc degeneration analyzed in this study were sourced from their respective genome-wide association studies (GWAS). MR analysis employed single nucleotide polymorphisms (SNPs) closely associated with disease as instrumental variables (IVs). The inverse variance weighted (IVW) method was employed as the primary statistical approach, complemented by MR-Egger, the Weighted median, Simple mode, and the Weighted mode for result validation. Comprehensive sensitivity analyses were performed to confirm the robustness of the results and assess for heterogeneity and horizontal pleiotropy. Results: Using the IVW method, this study revealed positive causal effects between 11 cerebrospinal fluid metabolites (CFMs) and intervertebral disc degeneration (IVDD), indicating that elevated levels of these 11 CFMs increase the risk of IVDD. Conversely, negative causal effects were identified for 6 CFMs, suggesting that higher levels of these CFMs have a protective effect against IVDD. Reverse MR analysis indicated 1 positive and 18 negative causal relationships between IVDD and CFMs. Conclusions: Our bidirectional Mendelian analysis provides compelling evidence of a causal relationship between CFMs and IVDD. These findings enhance our understanding of IVDD pathogenesis and highlight the potential for preventive therapies targeting CFMs. Further research is needed to clarify the mechanisms of these CFMs on IVDD. Full article

Background: Narcolepsy type 1 (NT1) is a rare neurological sleep disorder characterized by excessive daytime sleepiness and cataplexy. NT1 is thought to be caused by the loss of hypocretin-producing neurons in the hypothalamus due to autoimmunity. Since cerebrospinal fluid hypocretin testing is invasive and not always feasible in clinical practice, there is a critical need for less invasive biomarkers to improve diagnostic accuracy and accessibility. Very few studies have explored serum-based biomolecules that could serve as biomarkers for NT1. Methods: This study examines the differential abundance of serum metabolites in patients with NT1 using an LC-MS/MS-based comprehensive metabolomics approach. Results: An untargeted analysis identified a total of 1491 metabolites, 453 of which were differentially abundant compared to the control cohort. Ingenuity pathway analysis revealed that key pathways, such as the inflammatory response (p-value of 0.01, activation z-score of 0.5), generation and synthesis of reactive oxygen species (p-value of 0.0008, z-score of 1.3), and neuronal cell death (p-value of 0.04, z-score of 0.4), are predicted to be activated in NT1. A targeted analysis using parallel reaction monitoring validated 49 metabolites, including important downregulated metabolites such as uridine (fold change (FC) of 0.004), epinephrine (FC of 0.05), colchicine (FC of 0.2), corticosterone (FC of 0.3), and arginine (FC of 0.6), as well as upregulated metabolites such as p-cresol sulfate (FC of 2601.7), taurine (FC of 1315.4), inosine (FC of 429.7), and malic acid (FC of 7.9). Conclusions: Understanding the pathways identified in this study and further investigating the differentially abundant metabolites associated with them may pave the way for gaining insight into disease pathogenesis and developing novel therapeutic interventions. Full article

Background: Parkinson’s disorder (PD) affects around 1:500 individuals and is associated with enlarged ventricles and symptoms of normal pressure hydrocephalus (NPH). These features suggest disrupted cerebrospinal fluid (CSF) dynamics and folate metabolism. With L-DOPA treatment showing diminishing benefits over time, there is an urgent need to investigate upstream metabolic disruptions, including folate and tetrahydrobiopterin (BH4) pathways, in post-mortem CSF and brain tissue to understand their roles in PD pathogenesis. Methods: CSF and brain tissue from 20 PD patients (mean age 84 years; 55% male; disease duration 10–30 years) and 20 controls (mean age 82 years; 50% male) were analysed. Western and Dot Blots measured proteins and metabolites, spectroscopic assays assessed enzyme activities, BH4 and Neopterin levels were measured using ELISA, and levels of hydrogen peroxide, used as a proxy for reactive oxygen species, and calcium were quantified using horseradish peroxidase and flame photometry assays, respectively. ClinVar genetic data were analysed for variants in genes encoding key enzymes. Statistical significance was assessed using unpaired t-tests (p < 0.05). Results: All enzymes were significantly reduced in PD compared to controls (p < 0.01) except for methyltetrahydrofolate reductase (MTHFR), which was elevated (p < 0.0001). Enzymes were functional in control but undetectable in PD CSF except tyrosine hydroxylase (TH). BH4 and Neopterin were elevated in PD CSF (p < 0.0001, p < 0.001) but significantly reduced (p < 0.001) or unchanged in tissue. Peroxide was increased in both PD CSF (p < 0.001) and tissue (p < 0.0001) selectively inhibiting TH. Calcium was 40% higher in PD than controls (p < 0.05). No pathogenic variants in enzyme genes were found in ClinVar data searches, suggesting the observed deficiencies are physiological. Conclusions: We identified significant disruptions in folate and BH4 pathways in PD, with enzyme deficiencies, oxidative stress and calcium dysregulation pointing to choroid plexus dysfunction. These findings highlight the choroid plexus and CSF as key players in cerebral metabolism and promote further exploration of these as therapeutic targets to address dopaminergic dysfunction and ventricular enlargement in PD. Full article

Background: Bai Hu Tang (BHT) is a classic antipyretic in traditional Chinese medicine, however, there is little scientific evidence on the mechanism and material basis of its antipyretic effect. Methods: In LPS-induced febrile rats, after administration of BHT at 42 g/kg for half an hour, body temperature was measured at hourly intervals for 9 consecutive hours. Then, serum levels of TNF-α, IL-1β, and IL-6, and serum and cerebrospinal fluid (CSF) levels of AVP, cAMP, PGE2, Ca and CRH, and the remaining sera were used for metabolomics. These were then combined with network pharmacology methodology to further analyse the antipyretic effect of BHT and then dock key targets with differential components. Results: Administration of BHT to LPS-induced febrile rats significantly reduced elevated body temperature, TNF-α, IL-1β and IL-6 levels, but serum and CSF levels of AVP, cAMP, PGE2, Ca²⁺ and CRH were significantly elevated compared to the control group. Network pharmacological analyses indicated that the putative functional targets of BHT were regulation of immune responses, associated protein binding and inflammatory responses, and fine-tuning of phosphatase binding and activation of signalling pathways such as MAPK, PI3K, AKT, NF-kB, cAMP and inflammatory pathways. Metabolomic analysis showed that the antipyretic effect of BHT and its mechanism are likely to be involved in fatty acid metabolism, bile acid metabolism and amino acid metabolism in the organism, with L-arginine, glycyrrhetinic acid and N-acetylpentraxine as the main differential metabolites that play a significant role in heat recovery. The results also showed better docking of glycyrrhetinic acid with TNF-α, IL-6R, PTGS2. Conclusions: BHT provides a valuable adjunct to traditional clinical antipyretics by improving body temperature and metabolism and reducing inflammation. Full article

Anorexia nervosa (AN) is a severe psychiatric disorder characterized by substantial heritability and a high mortality rate among psychiatric disorders. While cerebrospinal fluid (CSF) metabolomics has emerged as a novel approach to investigating central nervous system pathologies, its specific causal relationship with anorexia nervosa remains to be fully elucidated. Using genome-wide association study (GWAS) summary statistics for human CSF metabolites and AN information from publicly available datasets, we performed a two-sample Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW) method as the primary approach, complemented by sensitivity analyses. Through a comprehensive analysis of 338 CSF metabolites, we identified six metabolites with significant causal relationships with AN risk. 1-stearoyl-2-linoleoyl-gpc (18:0/18:2) (OR = 1.09, 95% CI 1.00–1.18) and alpha-tocopherol (OR = 1.36, 95% CI 1.00–1.83) showed positive associations, increasing AN risk. Conversely, sphingomyelin (d18:1/20:0, d16:1/22:0) (OR = 0.86, 95% CI 0.77–0.95), 2,3-dihydroxy-2-methylbutyrate (OR = 0.92, 95% CI 0.86–0.98), N-acetylhistidine (OR = 0.92, 95% CI 0.86–0.98), and oxalate (ethanedioate) (OR = 0.83, 95% CI 0.73–0.94) had protective effects, reducing AN risk. Sensitivity analyses showed no evidence of horizontal pleiotropy or heterogeneity in the MR results. An MR directionality test and a Steiger filtering test confirmed the absence of reverse causality, thereby substantiating the robustness of our findings. These findings suggest that these CSF metabolites could serve as potential biomarkers for early AN detection and highlight novel therapeutic targets, potentially improving diagnosis and intervention strategies for this challenging disorder. Full article

Changes in the level of metabolites, small molecules that are intermediates produced by metabolism or catabolism, are associated with developing diseases. Metabolite signatures in body fluids such as plasma, cerebrospinal fluid, urine, and saliva are associated with Parkinson’s disease. Here, we discuss alteration of metabolites in the TCA cycle, pentose phosphate pathway, kynurenic network, and redox system. We also summarize the efforts of many research groups to differentiate between metabolite profiles that characterize PD motor progression and dyskinesia, gait and balance, and non-motor symptoms such as depression and cognitive decline. Understanding how changes in metabolites lead to progression in PD may allow for the identification of individuals at the earliest stage of the disease and the development of new therapeutic strategies. Full article

Multiple system atrophy (MSA) is a progressive neurodegenerative synucleinopathy. Differentiating MSA from other synucleinopathies, especially in the early stages, is challenging because of its overlapping symptoms with other forms of Parkinsonism. Thus, there is a pressing need to clarify the underlying biological mechanisms and identify specific biomarkers for MSA. The metabolic profile of cerebrospinal fluid (CSF) is known to be altered in MSA. To further investigate the biological mechanisms behind the metabolic changes, we created a network of altered CSF metabolites in patients with MSA and analysed these changes using bioinformatic software. Acknowledging the limitations of metabolomics, we incorporated proteomic data to improve the overall comprehensiveness of the study. Our in silico predictions showed elevated ROS, cytoplasmic inclusions, white matter demyelination, ataxia, and neurodegeneration, with ATP concentration, neurotransmitter release, and oligodendrocyte count predicted to be suppressed in MSA CSF samples. Machine learning and dimension reduction are important multi-omics approaches as they handle large amounts of data, identify patterns, and make predictions while reducing variance without information loss and generating easily visualised plots that help identify clusters, patterns, or outliers. Thus, integrated multiomics and machine learning approaches are essential for elucidating neurodegenerative mechanisms and identifying potential diagnostic biomarkers of MSA. Full article

Post-exertional malaise (PEM) is a defining condition of myalgic encephalomyelitis (ME/CFS). The concept requires that a provocation causes disabling limitation of cognitive and functional effort (“fatigue”) that does not respond to rest. Cerebrospinal fluid was examined as a proxy for brain metabolite and lipid flux and to provide objective evidence of pathophysiological dysfunction. Two cohorts of ME/CFS and sedentary control subjects had lumbar punctures at baseline (non-exercise) or after submaximal exercise (post-exercise). Cerebrospinal fluid metabolites and lipids were quantified by targeted Biocrates mass spectrometry methods. Significant differences between ME/CFS and control, non-exercise vs. post-exercise, and by gender were examined by multivariate general linear regression and Bayesian regression methods. Differences were found at baseline between ME/CFS and control groups indicating disease-related pathologies, and between non-exercise and post-exercise groups implicating PEM-related pathologies. A new, novel finding was elevated serine and its derivatives sarcosine and phospholipids with a decrease in 5-methyltetrahydrofolate (5MTHF), which suggests general dysfunction of folate and one-carbon metabolism in ME/CFS. Exercise led to consumption of lipids in ME/CFS and controls while metabolites were consumed in ME/CFS but generated in controls. In general, the frequentist and Bayesian analyses generated complementary but not identical sets of analytes that matched the metabolic modules and pathway analysis. Cerebrospinal fluid is unique because it samples the choroid plexus, brain interstitial fluid, and cells of the brain parenchyma. The quantitative outcomes were placed into the context of the cell danger response hypothesis to explain shifts in serine and phospholipid synthesis; folate and one-carbon metabolism that affect sarcosine, creatine, purines, and thymidylate; aromatic and anaplerotic amino acids; glucose, TCA cycle, trans-aconitate, and coenzyme A in energy metabolism; and vitamin activities that may be altered by exertion. The metabolic and phospholipid profiles suggest the additional hypothesis that white matter dysfunction may contribute to the cognitive dysfunction in ME/CFS. Full article

Brain and leptomeningeal metastases are complications of breast cancer with high rates of morbidity and mortality and have an estimated incidence of up to 30%. While National Comprehensive Cancer Network (NCCN) guidelines recommend screening for central nervous system metastasis in other neurotropic cancers such as non-small cell lung cancer, there are no such recommendations for asymptomatic breast cancer patients at any stage of disease. This review highlights ongoing studies into screening and diagnostics for breast cancer with brain and leptomeningeal metastasis (BCBLM) as they relate to patient outcomes and prognostication. These include imaging methods such as MRI with novel contrast agents with or without PET/CT, as well as ‘liquid biopsy’ testing of the cerebrospinal fluid and serum to analyze circulating tumor cells, genomic material, proteins, and metabolites. Given recent advances in radiation, neurosurgery, and systemic treatments for BCBLM, screening for CNS involvement should be considered in patients with advanced breast cancer as it may impact treatment decisions and overall survival. Full article

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Recent studies have highlighted the significant role of cerebrospinal fluid (CSF) in reflecting pathophysiological PD brain conditions by analyzing the components of CSF. Based on the published literature, we created a single network with altered metabolites in the CSF of patients with PD. We analyzed biological functions related to the transmembrane of mitochondria, respiration of mitochondria, neurodegeneration, and PD using a bioinformatics tool. As the proteome reflects phenotypes, we collected proteome data based on published papers, and the biological function of the single network showed similarities with that of the metabolomic network. Then, we analyzed the single network of integrated metabolome and proteome. In silico predictions based on the single network with integrated metabolomics and proteomics showed that neurodegeneration and PD were predicted to be activated. In contrast, mitochondrial transmembrane activity and respiration were predicted to be suppressed in the CSF of patients with PD. This review underscores the importance of integrated omics analyses in deciphering PD’s complex biochemical networks underlying neurodegeneration. Full article

Multiple sclerosis (MS) is a neurodegenerative and inflammatory disease of the central nervous system (CNS) that leads to a loss of myelin. There are three main types of MS: relapsing-remitting MS (RRMS) and primary and secondary progressive disease (PPMS, SPMS). The differentiation in the pathogenesis of these two latter courses is still unclear. The underlying mechanisms of MS are yet to be elucidated, and the treatment relies on immune-modifying agents. Recently, lipidomics and metabolomics studies using human biofluids, mainly plasma and cerebrospinal fluid (CSF), have suggested an important role of lipids and metabolites in the pathophysiology of MS. In this review, the results from studies on metabolomics and lipidomics analyses performed on biological samples of MS patients and MS-like animal models are presented and analyzed. Based on the collected findings, the biochemical pathways in human and animal cohorts involved were investigated and biological mechanisms and the potential role they have in MS are discussed. Limitations and challenges of metabolomics and lipidomics approaches are presented while concluding that metabolomics and lipidomics may provide a more holistic approach and provide biomarkers for early diagnosis of MS disease. Full article

The use of cerebrospinal fluid (CSF) in post-mortem (PM) toxicological analysis is an under-addressed topic, likely due to the technical complexity of the collection of a proper sample. However, it is a matrix of significant interest since it has similar chemical and physical properties to the blood and it is less exposed to risks like PM redistribution and diffusion due to its anatomical location. This study aimed to validate a sensitive analytical method for the quantification of drugs of abuse and their metabolites (i.e., cocaine, ketamine, amphetamine, MDPV, 6-monoacetylmorphine, morphine, codeine, and methadone) through liquid chromatography–tandem mass spectrometry (LC-MS/MS). CSF was collected through ventricular puncture, and 200 µL was deproteinated with acetonitrile (600 µL). Quantification was carried out, acquiring two MRM transitions for each compound in positive ionization mode. Chromatographic separation was achieved with a C18 column. Limits of quantification ranged from 0.05 to 5 ng/mL. Bias and precision were always within the acceptance criteria. Ion enhancement and suppression effects were observed depending on the substance. The method validated here was applied to a real case, proving to be suitable for PM analysis. CSF and blood were positive for methadone (460 vs. 280 ng/mL), cocaine (125 vs. 69 ng/mL), benzoylecgonine (4640 vs. 3160 ng/mL), and lorazepam (19 vs. 25 ng/mL). In the future, this will be useful for the evaluation of CSF as a valuable alternative matrix in PM investigations. Full article