Home Exploring cerebrospinal fluid metabolites, cognitive function, and brain atrophy: Insights from Mendelian randomization
Article Open Access

Exploring cerebrospinal fluid metabolites, cognitive function, and brain atrophy: Insights from Mendelian randomization

  • Qian Liu , Ling-bing Meng , Tian-qi Qi , Ya-Qing Ma and Guo-wei Liang ORCID logo EMAIL logo
Published/Copyright: August 4, 2025
Download Article (PDF)
Open Medicine
From the journal Open Medicine Volume 20 Issue 1

Abstract

Disruption of cerebrospinal fluid (CSF) metabolites affects brain function and cognition, potentially altering the brain structure. To elucidate the causal relationships between CSF metabolites and the neurological outcomes, we conducted a two-sample Mendelian randomization analysis. Genome-wide association data from 689 individuals of European descent provided exposure levels for metabolites, analyzed alongside gene associations for cognitive performance (N  =  257,841), brain atrophy measures (cortical surface area and thickness; N  =  51,665), and hippocampal volume (N  =  33,536). Our analysis identified 30 metabolites exhibiting causal associations with brain atrophy and cognitive function: 20 linked to cognition and 10 to structural atrophy. Notably, butyrate correlated strongest with the cortical surface area, bilirubin with the cortical thickness, methionine sulfoxide with the hippocampal volume, threonate with cognitive performance, while oxidized Cys-gly, N6-succinyladenosine, and N-acetylglucosamine were linked to fluid intelligence, prospective memory, and reaction time, respectively. Pathway analyses revealed that butanoate and niacinamide/niacin ester metabolism are significantly associated with brain atrophy and cognitive performance. These findings position CSF metabolites as promising therapeutic targets for neurodegenerative diseases, providing a causal framework to prioritize interventions. Experimental studies building on this genetic evidence hold potential to accelerate the development of mechanism-driven therapies targeting metabolic pathways in neurodegeneration.

Keywords: cerebrospinal fluid; metabolomics; cognition; brain atrophy; Mendelian randomization

1 Introduction

With increasing life expectancy, dementia has emerged as a significant global health challenge, with an estimated 150 million people projected to be affected by 2050 [1]. The brain starts changing years before clinical symptoms appear [2]. Early biomarkers help in studying the pathological mechanisms and potential prevention strategies.

In recent years, metabolomics research has revealed new insights into complex diseases such as diabetes, obesity, cancer, and Alzheimer’s disease (AD) [3,4,5,6], elucidating their disease mechanisms through the identification of relevant metabolites and discovering potential biomarkers for diagnosis and prognosis. Although most studies focus on blood or urine samples, cerebrospinal fluid (CSF) is particularly crucial for psychiatric and neurological disorders [7]. CSF can directly reflect physiological changes in the central nervous system. For example, in AD, CSF is an important source of biomarkers like amyloid-beta and phosphorylated tau [8]. A wealth of observational cohort studies have investigated the relationship between metabolites and brain structure and cognition, suggesting that these metabolites may have neuroprotective, anti-inflammatory, or other effects [9,10,11].

Due to the tendency for observational studies to encounter reverse causation and confounding effects, we employed Mendelian randomization (MR) using genetic variants as instrumental variables (IVs) based on Mendel’s law to explore causal relationships between exposure and outcome [12]. Cognitive function and brain atrophy markers are considered key features of AD and other forms of dementia [13,14], and a larger number of cases may be more suitable for dissecting potential causal relationships between CSF metabolites and dementia phenotypes.

This study aims to investigate 338 CSF metabolites closely associated with the onset and progression of AD. By identifying metabolites causally linked to AD, we seek to understand their biological significance and their feasibility as biomarkers or therapeutic agents. Therefore, in this study, we employ two-sample MR to assess causal relationships between CSF metabolite levels and measures of general cognitive function (with three additional domains of the fluid intelligence score, prospective memory result, and reaction time) and measures of brain atrophy (cerebral cortical surface area and thickness and hippocampal volume).

2 Method

2.1 Study design

We conducted a two-sample MR study, adhering to three hypotheses: (1) the IV is closely associated with the exposure of interest; (2) the IV is independent of confounding factors; and (3) the IV does not affect the outcome except through the exposure [15]. The data used in this study are summary statistics from genome-wide association studies (GWAS). The original studies obtained specific ethical approval and informed consent. The study design is illustrated in Figure 1.

Figure 1 Overview of MR analysis. Assumption 1, genetic instruments are strongly associated with the exposures of interest; Assumption 2, genetic instruments are independent of confounding factors; Assumption 3, genetic instruments are not associated with outcome and affect outcome only via exposures. IVW, inverse variance weighted; MR-PRESSO, MR-Pleiotropy RESidual sum and outlier; SNPs, single-nucleotide polymorphisms.
Figure 1

Overview of MR analysis. Assumption 1, genetic instruments are strongly associated with the exposures of interest; Assumption 2, genetic instruments are independent of confounding factors; Assumption 3, genetic instruments are not associated with outcome and affect outcome only via exposures. IVW, inverse variance weighted; MR-PRESSO, MR-Pleiotropy RESidual sum and outlier; SNPs, single-nucleotide polymorphisms.

2.2 Selection of IVs

Genetic instruments associated with 338 CSF metabolites were derived from recent GWAS studies. These studies performed genome-wide association analyses of 338 CSF metabolites in cognitively healthy participants with an average age of 60 years (data available for download from ftp://ftp.biostat.wisc.edu/pub/lu_group/Projects/MWAS/). Notably, this represents the most comprehensive report to date on genetic loci related to CSF metabolites, identifying nearly 1.8 million SNPs through genome-wide association scans and high-throughput metabolic profiling conducted by Panyard et al. [16]. The detailed names of the 338 metabolites are listed in Table S1, with metabolites named X having unknown chemical properties. Specifically, the study included 689 participants, of whom 532 were from the Wisconsin Alzheimer’s Disease Research Center (WADRC) and 168 were from the Wisconsin Registry for Alzheimer’s Prevention, each providing unique CSF samples for metabolite analysis. Selection criteria for WADRC participants included age ≥45 years, decision-making capacity, and ability to fast for 12 h, with exclusion criteria such as specific medical histories including renal dysfunction, congestive heart failure, and major neurological disorders (excluding dementia).

To meet hypothesis (1), we identified IVs related to blood metabolites through rigorous screening criteria from multiple perspectives. Given the moderate number of SNPs associated with metabolites, we selected a stringent significance threshold of p < 5 × 10−8 to choose SNPs associated with the metabolites. We used a p-value threshold of less than 5 × 10⁻⁸ for metabolite GWAS IVs, as suggested by Burgess and Thompson [26], to strengthen genetic effects, though this could exclude SNPs with minor associations. Subsequently, we aggregated SNPs by eliminating linkage disequilibrium (LD, R 2 > 0.001 and within 10,000 kb). To minimize weak instrument bias, we computed the R 2 and F statistics for each SNP. The R 2 and F statistics were calculated as follows:

R 2 = 2 × β 2 × EAF × ( 1 − EAF ) [ 2 × β 2 × ( 1 − EAF ) + 2 × ( se ( β ) ) 2 × N × EAF × ( 1 − EAF ) ] ,

F = N − k − 1 k × R 2 1 − R 2 .

Here, β represents the effect size of the target genetic variation, EAF denotes the allele frequency of the target genetic variation, se(β) indicates the standard error of the effect size of the target genetic variation, R 2 is the coefficient of determination for the IVs explaining the exposure level in the regression equation, N is the sample size of the exposure, and k is the number of SNPs (IVs). SNPs with F < 10 are defined as poor genetic variations and are excluded [17]. Next, we filtered SNPs associated with metabolites from the results (p < 5 × 10−8). We further matched SNPs for exposure and outcome, removing those with reverse effects or allele inconsistency (e.g., A/G versus A/C). Then, to satisfy hypothesis (3), we excluded SNPs from IVs associated with the outcome (p < 5 × 10−5). Finally, causal inference analysis was performed on metabolites with two or more SNPs [18].

2.3 Cognitive-related traits

Cognitive performance was evaluated using a meta-analysis weighted by sample size, utilizing data from the Cognitive Genomics Consortium (COGENT, n = 35,295) and the UK Biobank (n = 222,543), and extracting genetic association statistics pertaining to general cognitive performance from the most recent GWAS conducted on individuals of European ancestry (N = 257,841) [19]. Participants ranged in age from 16 to 102 years and had no history of stroke or dementia. In COGENT, cognitive performance was defined as the first unrotated principal component score derived from at least three different neuropsychological tests included in the study. In the UK Biobank, verbal-numerical reasoning (VNR) was assessed using 13 multiple-choice questions, with VNR scores reflecting the number of correctly answered questions within 2 min, designed to measure fluid intelligence. This assessment has been demonstrated to possess adequate reliability and validity [19,20].

GWAS data on fluid intelligence score (N = 149,051) and prospective memory score (N = 152,605) were obtained from the UK Biobank, evaluated using fluid intelligence questions and image tests, respectively [21]. Data for reaction time (N = 330,069) came from a study on genetic loci related to general cognitive function conducted by the Centre for Cognitive Ageing and Epidemiology at the University of Edinburgh [22]. This measure is based on the total time taken by the participants to correctly complete card-matching tasks.

2.4 Measurements of brain atrophy

Genetic associations with the cortical surface area (mm²) and thickness (mm) were identified using a genome-wide meta-analysis of brain T1-weighted magnetic resonance imaging (MRI) data from 51,665 healthy individuals of European ancestry aged 3.3–91.4 years across 60 cohorts, conducted by the Enhancing Neuro Imaging Genetics through Meta Analysis (ENIGMA) consortium [23]. Among these 60 cohorts, less than 1% of the participants had psychiatric disorders in the included case–control studies, with nearly all others being healthy. Cortical surface area was measured at the gray–white matter boundary, and thickness was defined as the average distance between the white matter and pial surface. The total surface area and mean thickness were calculated for each participant. Genetic associations were assessed using additive models within each cohort, adjusting for age, age squared, sex, interaction of sex with age and age squared, the first four multidimensional scaling components, diagnostic status (where applicable in case–control cohorts), and scanner-specific variables.

Genetic data for hippocampal volume were derived from a GWAS meta-analysis conducted by the ENIGMA and CHARGE consortia across 65 study centers, analyzing high-resolution brain MRI scans from 33,536 healthy individuals aged 11–98 years [24]. Bilateral average hippocampal volume (mm³) was defined as the mean volume of the left and right hippocampus. Genetic associations were evaluated within each study center, adjusting for age, age squared, sex, intracranial volume, four multidimensional scaling components, and diagnostic status. For studies involving data from multiple centers or scanners, adjustments were made for center effects, and mixed-effects models were used to account for familial relationships pertaining to family data.

2.5 Statistical analysis

Causal relationships between CSF metabolites and brain atrophy and cognitive decline were primarily assessed based on results from inverse variance weighting (IVW). The IVW estimates are derived from meta-analyses of the Wald ratio for all genetic variants [24]. IVW assumes no horizontal pleiotropy across all SNPs, providing the most accurate assessment of causal relationships [25]. Initially, we used IVW-based estimates to screen CSF metabolites causally linked to brain atrophy and cognitive decline. To ensure robust findings, we applied two additional methods to further evaluate metabolites with significant IVW estimates (p < 0.05). MR-Egger, weighted median (WM), and weighted mode methods were employed as complementary analyses. These methods offer more robust estimates under relaxed assumptions; WM allows for less than 50% of the SNPs to be invalid, while MR-Egger provides tests for horizontal pleiotropy and heterogeneity in the presence of all SNPs having horizontal pleiotropy [26]. Weighted mode considers each genetic variant’s contribution to causal inference more precisely, making it suitable for handling complex weight data [17]. The false discovery rate (FDR) correction was applied using a standard and well-established procedure to account for multiple comparisons and control the false discovery rate in statistical analyses.

Sensitivity analysis is crucial as it allows for examination of potential violations of horizontal pleiotropy and heterogeneity that could seriously bias MR estimates. Horizontal pleiotropy is observed when IV influences outcomes through pathways other than the exposure of interest. Therefore, several tests were conducted to ensure the credibility of estimates. In this study, we employed three methods to detect and correct for heterogeneity and pleiotropy, including Cochran’s Q test and MR-Egger intercept test. Heterogeneity was deemed present if Cochran’s Q test yielded a p-value <0.05 [27]. The MR-Egger intercept was calculated to assess directional pleiotropy and bias due to invalid IVs [26]. For robustness of results, we conducted leave-one-out (LOO) analysis, where each SNP was sequentially removed and MR analysis was rerun to evaluate the impact of individual SNPs [26].

To summarize, we systematically screened CSF metabolites potentially associated with brain atrophy and cognitive decline using several criteria: (1) significant p-values in the main analysis (p < 0.05 by IVW). (2) Consistent direction of beta values across four MR methods. (3) No heterogeneity or horizontal pleiotropy observed in MR results. (4) Minimal disruption of MR estimates by individual SNPs.

2.6 Reverse analysis

In order to investigate potential reverse causation, we also examined the relationships between genetically influenced cognitive performance and brain atrophy markers with 338 CSF metabolites. To achieve this, we extracted independent genetic variants significantly associated with cognitive performance, cortical surface area, and thickness, as well as hippocampal volume from the same GWAS dataset, utilizing these variants as IVs in our primary analyses. SNPs associated with the cortical surface area and thickness were excluded to mitigate potential pleiotropic effects. All analyses were performed using R (v3.6.3) statistical software (R Foundation for Statistical Computing, Vienna, Austria). MR analyses were conducted using the R package “TwoSample MR.” A p-value of 0.05 was considered statistically significant.

  1. Ethics and consent declarations: This study utilized publicly available GWAS summary statistics and did not involve new human subject experimentation. Therefore, institutional ethics approval and individual participant consent were not required. The original studies obtained ethical approval in accordance with the Declaration of Helsinki.

3 Results

3.1 MR results

Following strict control of the IV P1 threshold (5e-8) and removal of linkage disequilibrium, we proceeded with further analysis using 228 out of the 338 metabolites, as outlined in Table S1. From the screened exposure-related SNP data, SNPs corresponding to the outcome were extracted to ensure analysis consistency and comparability based on the same SNP set. A threshold P2 (5e-5) was applied to exclude SNPs highly correlated with the outcome, aiming to mitigate confounding effects or spurious associations. SNP datasets demonstrating no reverse causation, identified through Steiger test results, were used to finalize the IVs for analysis (refer to Table S2). All F-statistics for SNPs associated with metabolites exceeded 10, confirming the strength of the IVs. Subsequent to IVW analysis, combined with complementary and sensitivity analyses, we pinpointed 30 metabolites potentially causally associated with brain atrophy and cognitive function.

Ten metabolites meeting strict screening criteria are associated with brain atrophy, as shown in Figure 2. Methionine sulfoxide and 1-palmitoyl-2-linoleoyl-gpc (16:0/18:2) show increased levels correlated with smaller hippocampal volume. Proline, 1-palmitoyl-2-oleoyl-gpc (16:0/18:1), choline phosphate levels, isobutyrylcarnitine (c4), butyrate (4:0), and X-23308 are correlated with the cortical surface area. Increased bilirubin (z,z) and X-11612 levels are associated with thicker cortical thickness. Detailed results of all MR analyses for CSF metabolites and brain atrophy are presented in Table S3.

Figure 2 Association of CSF metabolites with measures of brain atrophy.
Figure 2

Association of CSF metabolites with measures of brain atrophy.

Twenty metabolites meeting stringent screening criteria associated with cognitive function are detailed in Figure 3. Acisoga, hippurate, phenylacetylglutamine, and threonate are correlated with cognitive performance. Acetylcarnitine (c2), Cys-gly, oxidized, ribulonate, threonate, and X-11787 are associated with fluid intelligence scores. Cholesterol, 1-methylnicotinamide, hippurate, and N6-succinyladenosine are associated with prospective memory. N-Acetylglucosamine, oxalate, N-acetylhistidine, 2,3-dihydroxy-2-methylbutyrate, ascorbate, 4-chlorobenzoic acid, and sphingomyelin (d18:1/20:0, d16:1/22:0) are associated with the reaction time. Comprehensive results of all MR analyses on CSF metabolites and cognitive function are provided in Table S4. The substances causing these changes include N-acetylglucosamine and oxalate, both of which, after adjustment using FDR multiple comparisons, have adjusted p-values less than 0.05.

Thirty metabolites exhibited statistically significant estimated values from IVW (p  <  0.05), with consistent direction and magnitude of estimates across IVW, MR-Egger, and WM approaches (Tables S3 and S4). Cochran’s Q test (p  >  0.05) and MR-Egger intercept test (p  >  0.05) provided robust evidence against heterogeneity and pleiotropy (Tables 1 and 2). LOO analysis supported the absence of MR estimation bias due to individual SNPs (Figure S1).

Table 1

Heterogeneity and pleiotropy of CSF metabolites on brain atrophy

Exposure Outcome Heterogeneity test Pleiotropy test
MR Egger Q P value MR-Egger intercept P value
Methionine sulfoxide Left parahippocampal volume 1.751 0.781 0.000 0.999
1-Palmitoyl-2-linoleoyl-gpc (16:0/18:2) Right parahippocampal volume 50.357 0.105 −0.002 0.740
Proline Cortical surface area 0.586 0.900 −0.001 0.940
1-Palmitoyl-2-oleoyl-gpc (16:0/18:1) Cortical surface area 0.007 0.931 −0.006 0.892
Choline phosphate Cortical surface area 14.510 0.753 0.016 0.369
Isobutyrylcarnitine (c4) Cortical surface area 2.483 0.289 −0.002 0.929
Butyrate (4:0) Cortical surface area 19.452 0.909 0.004 0.849
X-23308 Cortical surface area 7.579 0.476 −0.023 0.265
Bilirubin (z,z) Cortical thickness 1.515 0.218 −0.001 0.811
X-11612 Cortical thickness 12.429 0.257 0.000 0.830
Table 2

Heterogeneity and pleiotropy of CSF metabolites on cognitive function

Exposure Outcome Heterogeneity test Pleiotropy test
MR Egger Q P value MR-Egger intercept P value
Acisoga Cognitive performance 10.838 0.764 −0.014 0.146
Hippurate Cognitive performance 76.364 0.158 −0.002 0.606
Phenylacetylglutamine Cognitive performance 2.976 0.812 −0.007 0.110
Threonate Cognitive performance 39.203 0.148 0.001 0.811
Acetylcarnitine (c2) Fluid intelligence score 25.906 0.210 0.008 0.564
Cys-gly, oxidized Fluid intelligence score 3.986 0.679 −0.001 0.938
Ribulonate Fluid intelligence score 1.831 0.767 0.011 0.515
Threonate Fluid intelligence score 40.427 0.120 −0.001 0.860
X-11787 Fluid intelligence score 3.518 0.475 0.003 0.814
Cholesterol Prospective memory result 15.087 0.589 0.001 0.743
1-Methylnicotinamide Prospective memory result 12.953 0.676 −0.002 0.756
Hippurate Prospective memory result 58.792 0.723 0.000 0.942
N6-succinyladenosine Prospective memory result 0.092 0.762 0.003 0.886
N-acetylglucosamine Reaction time 11.947 1.000 0.000 0.964
Oxalate Reaction time 18.912 1.000 0.000 0.352
N-acetylhistidine Reaction time 3.346 1.000 −0.001 0.290
2,3-dihydroxy-2-methylbutyrate Reaction time 13.532 1.000 0.000 0.552
Ascorbate (vitamin c) Reaction time 8.217 1.000 0.000 0.958
4-Chlorobenzoic acid Reaction time 6.364 0.998 0.000 0.525
Sphingomyelin (d18:1/20:0, d16:1/22:0) Reaction time 0.725 1.000 0.000 0.729

3.2 Reverse analysis

In total, 147, 35, 42, 3, 12, 6, and 13 SNPs were, respectively, identified as associated with cognitive performance, reaction time, fluid intelligence score, prospective memory result, cortical surface area, cortical thickness, and hippocampal volume, which also appeared in CSF metabolite GWAS. Using the IVW method, changes in choline phosphate, hippurate, dimethylmalonic acid, homoarginine, citramalate, inosine, 3-hydroxy-3-methylglutarate, pyridoxate, myo-inositol, N-acetylglutamate, glycerol, argininate, isovalerate (i5:0), and X-12104 metabolites associated with cognitive performance were detected (Table S7). Comprehensive results of all MR analyses for cognitive performance and metabolites are presented in Table S8.

3.3 Metabolic pathway analysis

Metabolic pathway analysis based on metabolites identified two important metabolic pathways associated with brain atrophy and cognitive performance (Table S9). Our results indicate that “butanoate metabolism” (p = 0.0376) is associated with improvement in brain atrophy (Figure 4a), and “niacinamide and niacin ester metabolism” is associated with cognitive function (p = 0.0283) (Figure 4b).

Figure 3 Association of CSF metabolites with measures of cognitive function.
Figure 3

Association of CSF metabolites with measures of cognitive function.

Figure 4 Potential metabolic pathways associated with brain atrophy and cognitive function. (a) Potential metabolic pathways involved in changes related to brain atrophy in MR positive analysis (based on metabolites). (b) Potential metabolic pathways involved in changes related to cognitive function in MR positive analysis (based on metabolites). Based on Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The color and size of each circle represent the p-value from topological analysis (yellow: higher p-value, red: lower p-value) and pathway impact score (larger circles indicate higher impact scores).
Figure 4

Potential metabolic pathways associated with brain atrophy and cognitive function. (a) Potential metabolic pathways involved in changes related to brain atrophy in MR positive analysis (based on metabolites). (b) Potential metabolic pathways involved in changes related to cognitive function in MR positive analysis (based on metabolites). Based on Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The color and size of each circle represent the p-value from topological analysis (yellow: higher p-value, red: lower p-value) and pathway impact score (larger circles indicate higher impact scores).

4 Discussion

We identified 30 metabolites potentially and causally associated with brain atrophy and cognitive function, including 27 with known chemical compositions and 3 with unknown identities. The 27 known metabolites span categories such as amino acids, peptides, lipids, nucleic acids, vitamins, carbohydrates, and xenobiotics. Metabolic pathway analysis revealed two key pathways associated with brain atrophy and cognitive function: “butanoate metabolism” is linked to improvement in brain atrophy, and “niacinamide and niacin ester metabolism” is associated with cognitive performance. Additionally, there is a reverse causality between hippurate and cognitive performance.

The hippocampus is a crucial neural structure in the brain, particularly essential for learning and memory functions. Changes in its volume are typically associated with cognitive decline and neurodegenerative diseases such as AD. Generally, a reduction in the hippocampal volume is considered an early sign of cognitive decline. Our study found that increases in methionine sulfoxide and 1-palmitoyl-2-linoleoyl-gpc (16:0/18:2) are correlated with decreased hippocampal volume, consistent with the previous research findings. Methionine sulfoxide is an oxidized form of sulfur-containing amino acid, commonly associated with oxidative stress and antioxidant processes [28]. Methionine sulfoxide has also been reported to be closely related to the occurrence, development, and effective treatment of AD [29]. A specific phospholipid called 16:0/18:2, which is one of the main components of the cell membrane, may play an important role in cell signal transduction, lipid metabolism, and neuroprotection.

The cortical surface area of the brain refers to the total surface area of the outer gray matter, serving as a critical indicator of the brain structure and functional development. Studies indicate that the cortical surface area may be affected in AD patients, particularly in the early stages of the disease. Cortical atrophy and thinning are observed in AD patients, possibly linked to pathological processes such as neuronal loss, synaptic damage, and brain inflammation [30]. Proline primarily functions as an amino acid involved in protein structural stability and antioxidative effects in organisms, and is a neurotoxin associated with schizophrenia [31]. Our research has found a correlation between proline and the reduced cortical surface area, consistent with its detrimental role in neurodegenerative diseases. Isobutyrylcarnitine (C4), a short-chain acylcarnitine, is the most abundant carnitine in the human body. Studies suggest that levels of isobutyryl-l-carnitine in blood or plasma decrease in traumatic brain injury patients [32,33], consistent with our finding that lower levels of isobutyrylcarnitine (C4) correlate with smaller cortical surface area. Bilirubin’s antioxidant activity is particularly important for the brain, preventing excitotoxicity and neuronal death by clearing superoxide radicals during N-methyl-d-aspartate neurotransmission [34]. Similarly, our research correlates higher bilirubin levels with larger cortical surface area. Phospholipid 1-palmitoyl-2-oleoyl-gpc (16:0/18:1) also affects the cortical surface area by participating in the cell membrane structure and function. Choline phosphate is involved in phospholipid biosynthesis, impacting membrane stability and function. Butyric acid, a short-chain fatty acid, is metabolized in mitochondria through fatty acid metabolism as an energy source. Its role in the intestine and potential impact on overall health are supported by existing research, with lower butyric acid levels appearing correlated with multisystem atrophy [35]. Metabolomic pathway analysis reveals a significant association between butyric acid metabolism and brain atrophy, suggesting a potential beneficial role in neuroprotection and brain health via gut microbiota synthesis.

Cognitive performance, fluid intelligence scores, prospective memory outcomes, and reaction times are highly significant in studying cognitive functions, psychology, and neuroscience. Among these related CSF metabolites, acetylcarnitine (C2) participates in energy metabolism processes, potentially aiding in maintaining neuronal function and protecting the nervous system from damage [36]. Compounds such as Cys-gly, oxidized forms, and ascorbate (vitamin C) may benefit brain health through anti-oxidative and anti-inflammatory processes [37,38]. 1-Methylnicotinamide, the main metabolite of nicotinamide, has been reported to be associated with neuroprotection and can improve cognitive deficits [39]. Consistent with these findings, our results indicate that 1-methylnicotinamide leads to changes in prospective memory results. In studies of neuroprotection and cognitive function, threonate has shown significant advantages in improving cognitive abilities and memory [40]. Similarly, our research findings indicate that an increase in threonate enhances cognitive performance and fluid intelligence scores. Hippurate levels decrease in cognitive impairment disorders [41], which aligns with our finding that it alters cognitive performance and fluid intelligence scores. Phenylacetylglutamine and N-acetylhistidine are metabolites of amino acids. Ribulonate participates in the metabolic pathway of ribose. N6-Succinyladenosine is an adenosine analogue that may be involved in protein synthesis or energy metabolism pathways. Cholesterol and sphingomyelin (d18:1/20:0, d16:1/22:0) are lipids involved in the cell membrane structure and signal transduction. 4-Chlorobenzoic acid is a chlorinated benzoic acid used in chemical research or pharmaceutical synthesis. Oxalate participates in calcium metabolism and stone formation. These compounds have shown certain correlations with cognitive functions related to the brain in our research. Notably, two compounds remained significantly associated with the reaction time after FDR correction, highlighting their potential biological relevance. N-Acetylglucosamine, a biologically significant monosaccharide, plays a critical role in cellular processes, and its post-translational modifications may influence neuronal function and contribute to the pathogenesis of neurodegenerative diseases [42]. Oxalate, a naturally occurring organic compound primarily derived from dietary sources such as vegetables, legumes, and nuts, exhibits strong chelating properties and potential neurotoxicity. Consequently, tight regulation of its concentration in CSF may be essential to prevent neuronal damage [43]. In line with these findings, our results demonstrate that both N-acetylglucosamine and oxalate are negatively associated with reaction time, suggesting a potential link between these metabolites and cognitive processing speed.

In our reverse analysis, we found that only cognitive performance leads to changes in CSF metabolites, whereas other factors such as cortical area, thickness, hippocampal volume, fluid intelligence scores, brain cognition, prospective memory outcomes, and reaction times did not affect CSF metabolites. These two metabolites are worth noting. Elevated levels of hippurate are associated with the risk of age-related cognitive impairment, possibly due to an increase in hippurate following a high polyphenol diet, which enhances anti-inflammatory and antioxidative effects [41]. A high polyphenol diet appears to be the best dietary approach for preventing or delaying cognitive decline [44]. Additionally, from the perspective of gut microbiota, cognitive impairment significantly disrupts the composition and function of intestinal microbiota, where intestinal microbiota are involved in the synthesis and metabolism of hippurate [45]. Choline phosphate plays a crucial role in the synthesis of essential phospholipids for the human brain [46]. Higher levels of choline in brain metabolites are associated with the onset of psychiatric disorders [47]. Choline phosphate in the CSF is correlated with cognitive performance, though specific mechanisms require further research.

5 Advantages and limitations

To the best of our knowledge, this study represents the first comprehensive investigation of causal relationships between CSF metabolites and both cognitive function and structural brain atrophy. By employing a two-sample MR design (including bidirectional MR studies), we maximally avoided the pitfalls of reverse causation and residual confounding in observational studies. Second, this MR analysis extensively incorporates genetic variables, enabling us to make effective causal inferences. Finally, bidirectional MR design largely mitigates reverse causation and residual confounding factors [48]. However, several limitations need consideration in interpreting the results. First, the biological roles of certain identified metabolites and their associated pathways in cortical development and cognitive processes remain incompletely characterized, potentially constraining mechanistic interpretations of the MR findings. Second, as the analysis was restricted to European-ancestry populations, generalizability to other ethnic groups may be limited. Another limitation of the study is that the chemical properties of metabolites such as X-23308 and X-11612 remain unknown, which may affect the comprehensive interpretation of their roles and mechanisms.

6 Conclusion

In summary, this MR study establishes robust causal links between CSF metabolites and genetic determinants, while demonstrating their associations with cognitive function and structural brain metrics, including cortical and hippocampal volumes. These findings collectively underscore the potential role of CSF metabolites in modulating neurocognitive health. Future studies should prioritize multi-ethnic cohorts and longitudinal designs to strengthen causal inference, thereby advancing biomarker discovery for early diagnosis and disease monitoring in neurodegenerative disorders.

# These authors contributed equally to this work and share first authorship.

Acknowledgments

None.

  1. Funding information: This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

  2. Author contributions: G.W.L. conceived the study and supervised research; Q.L. and Y.Q.M. designed the methodology; Q.L. and L.B.M. performed data analysis. All authors contributed to data interpretation. Q.L. and L.B.M. drafted the manuscript; G.W.L., T.Q.Q., and L.B.M. provided critical revisions. All authors reviewed the manuscript.

  3. Conflict of interest: The authors declare no competing interests.

  4. Data availability statement: The datasets generated or analyzed during this study are included in the supplementary material or the data repositories listed in the methods.

References

[1] Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396:413–46. 10.1016/s0140-6736(20)30367-6.Search in Google Scholar

[2] Beason-Held LL, Goh JO, An Y, Kraut MA, O’Brien RJ, Ferrucci L, et al. Changes in brain function occur years before the onset of cognitive impairment. J Neurosci. 2013;33:18008–14. 10.1523/jneurosci.1402-13.2013.Search in Google Scholar PubMed PubMed Central

[3] Jin Q, Ma RCW. Metabolomics in diabetes and diabetic complications: insights from epidemiological studies. Cells. 2023;10:2832. 10.3390/cells10112832.Search in Google Scholar PubMed PubMed Central

[4] Oberbach A, Blüher M, Wirth H, Till H, Kovacs P, Kullnick Y, et al. Combined proteomic and metabolomic profiling of serum reveals association of the complement system with obesity and identifies novel markers of body fat mass changes. J Proteome Res. 2011;10:4769–88. 10.1021/pr2005555.Search in Google Scholar PubMed

[5] Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature. 2009;457:910–4. 10.1038/nature07762.Search in Google Scholar PubMed PubMed Central

[6] Trushina E, Dutta T, Persson XM, Mielke MM, Petersen RC. Identification of altered metabolic pathways in plasma and CSF in mild cognitive impairment and Alzheimer’s disease using metabolomics. PLoS One. 2013;8:e63644. 10.1371/journal.pone.0063644.Search in Google Scholar PubMed PubMed Central

[7] Schwarz E, Bahn S. Biomarker discovery in psychiatric disorders. Electrophoresis. 2008;29:2884–90. 10.1002/elps.200700710.Search in Google Scholar PubMed

[8] Olsson B, Lautner R, Andreasson U, Öhrfelt A, Portelius E, Bjerke M, et al. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol. 2016;15:673–84. 10.1016/s1474-4422(16)00070-3.Search in Google Scholar

[9] Jiang YM, Long LL, Zhu XY, Zheng H, Fu X, Ou SY, et al. Evidence for altered hippocampal volume and brain metabolites in workers occupationally exposed to lead: a study by magnetic resonance imaging and (1)H magnetic resonance spectroscopy. Toxicol Lett. 2008;181:118–25. 10.1016/j.toxlet.2008.07.009.Search in Google Scholar PubMed PubMed Central

[10] Meier TB, Drevets WC, Wurfel BE, Ford BN, Morris HM, Victor TA, et al. Relationship between neurotoxic kynurenine metabolites and reductions in right medial prefrontal cortical thickness in major depressive disorder. Brain Behav Immun. 2016;53:39–48. 10.1016/j.bbi.2015.11.003.Search in Google Scholar PubMed PubMed Central

[11] Scott AS, Nashid HC, Usman AK, Beatriz P, Martin AS, Iris A, et al. Imaging patients with psychosis and a mouse model establishes a spreading pattern of hippocampal dysfunction and implicates glutamate as a driver. Neuron. 2013;78:81–93. 10.1016/j.neuron.2013.02.011.Search in Google Scholar PubMed PubMed Central

[12] Peggy S, Fabiola DGM, Cristian P, Anna K. Mendelian randomization as an approach to assess causality using observational data. J Am Soc Nephrol. 2016;27:2257–69. 10.1681/ASN.2016010098.Search in Google Scholar PubMed PubMed Central

[13] Jessen F, Amariglio RE, van Boxtel M, Breteler M, Ceccaldi M, Chételat G, et al. A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer’s disease. Alzheimers Dement. 2014;10:844–52. 10.1016/j.jalz.2014.01.001.Search in Google Scholar PubMed PubMed Central

[14] Pini L, Pievani M, Bocchetta M, Altomare D, Bosco P, Cavedo E, et al. Brain atrophy in alzheimer’s disease and aging. Ageing Res Rev. 2016;30:25–48. 10.1016/j.arr.2016.01.002.Search in Google Scholar PubMed

[15] Boef AG, Dekkers OM, le Cessie S. Mendelian randomization studies: a review of the approaches used and the quality of reporting. Int J Epidemiol. 2015;44:496–511. 10.1093/ije/dyv071.Search in Google Scholar PubMed

[16] Panyard DJ, Kim KM, Darst BF, Deming YK, Zhong X, Wu Y, et al. Cerebrospinal fluid metabolomics identifies 19 brain-related phenotype associations. Commun Biol. 2021;4:63. 10.1038/s42003-020-01583-z.Search in Google Scholar PubMed PubMed Central

[17] Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013;37:658–65. 10.1002/gepi.21758.Search in Google Scholar PubMed PubMed Central

[18] Gill D, Brewer CF, Monori G, Trégouët DA, Franceschini N, Giambartolomei C, et al. Effects of genetically determined iron status on risk of venous thromboembolism and carotid atherosclerotic disease: a Mendelian randomization study. J Am Heart Assoc. 2019;8:e012994. 10.1161/jaha.119.012994.Search in Google Scholar

[19] Lee JJ, Wedow R, Okbay A, Kong E, Maghzian O, Zacher M, et al. Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals. Nat Genet. 2018;50:1112–21. 10.1038/s41588-018-0147-3.Search in Google Scholar PubMed PubMed Central

[20] Fawns-Ritchie C, Deary IJ. Reliability and validity of the UK Biobank cognitive tests. PLoS One. 2020;15:e0231627. 10.1371/journal.pone.0231627.Search in Google Scholar PubMed PubMed Central

[21] Haworth S, Mitchell R, Corbin L, Wade KH, Dudding T, Budu-Aggrey A, et al. Apparent latent structure within the UK Biobank sample has implications for epidemiological analysis. Nat Commun. 2019;10:333. 10.1038/s41467-018-08219-1.Search in Google Scholar PubMed PubMed Central

[22] Davies G, Lam M, Harris SE, Trampush JW, Luciano M, Hill WD, et al. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. Nat Commun. 2018;9:2098. 10.1038/s41467-018-04362-x.Search in Google Scholar PubMed PubMed Central

[23] Katrina LG, Neda J, Jodie NP, Lucía C-C, Janita B, Derrek PH, et al. The genetic architecture of the human cerebral cortex. Science. 2020;367:eaay6690. 10.1126/science.aay6690.Search in Google Scholar PubMed PubMed Central

[24] Hibar DP, Adams HHH, Jahanshad N, Chauhan G, Stein JL, Hofer E, et al. Novel genetic loci associated with hippocampal volume. Nat Commun. 2017;8:13624. 10.1038/ncomms13624.Search in Google Scholar PubMed PubMed Central

[25] Pierce BL, Burgess S. Efficient design for Mendelian randomization studies: subsample and 2-sample instrumental variable estimators. Am J Epidemiol. 2013;178:1177–84. 10.1093/aje/kwt084.Search in Google Scholar PubMed PubMed Central

[26] Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol. 2017;32:377–89. 10.1007/s10654-017-0255-x.Search in Google Scholar PubMed PubMed Central

[27] Cohen JF, Chalumeau M, Cohen R, Korevaar DA, Khoshnood B, Bossuyt PM. Cochran’s Q test was useful to assess heterogeneity in likelihood ratios in studies of diagnostic accuracy. J Clin Epidemiol. 2015;68:299–306. 10.1016/j.jclinepi.2014.09.005.Search in Google Scholar PubMed

[28] Suzuki S, Kodera Y, Saito T, Fujimoto K, Momozono A, Hayashi A, et al. Methionine sulfoxides in serum proteins as potential clinical biomarkers of oxidative stress. Sci Rep. 2016;6:38299. 10.1038/srep38299.Search in Google Scholar PubMed PubMed Central

[29] Schöneich C. Methionine oxidation by reactive oxygen species: reaction mechanisms and relevance to Alzheimer’s disease. Biochim Biophys Acta. 2005;1703:111–9. 10.1016/j.bbapap.2004.09.009.Search in Google Scholar PubMed

[30] Anders MF, Linda M, Dominic H, Anders MD, Kristine, BW. What is normal in normal aging? Effects of aging, amyloid and Alzheimer’s disease on the cerebral cortex and the hippocampus. Prog Neurobiol 2014;118:1–20. 10.1016/j.pneurobio.2014.02.0064.Search in Google Scholar

[31] Patriarca EJ, Cermola F, D’Aniello C, Fico A, Guardiola O, De Cesare D, et al. The Multifaceted roles of proline in cell behavior. Front Cell Dev Biol. 2021;9:728576. 10.3389/fcell.2021.728576.Search in Google Scholar PubMed PubMed Central

[32] Makarova E, Makrecka-Kuka M, Vilks K, Volska K, Sevostjanovs E, Grinberga S, et al. Decreases in circulating concentrations of long-chain acylcarnitines and free fatty acids during the glucose tolerance test represent tissue-specific insulin sensitivity. Front Endocrinol (Lausanne). 2019;10:870. 10.3389/fendo.2019.00870.Search in Google Scholar PubMed PubMed Central

[33] Jeter CB, Hergenroeder GW, Ward 3rd NH, Moore AN, Dash PK. Human mild traumatic brain injury decreases circulating branched-chain amino acids and their metabolite levels. J Neurotrauma. 2013;30:671–9. 10.1089/neu.2012.2491.Search in Google Scholar PubMed

[34] Vasavda C, Kothari R, Malla AP, Tokhunts R, Lin A, Ji M, et al. Bilirubin links heme metabolism to neuroprotection by scavenging superoxide. Cell Chem Biol. 2019;26:1450–60.e1457. 10.1016/j.chembiol.2019.07.006.Search in Google Scholar PubMed PubMed Central

[35] Voigt RM, Wang Z, Brown JM, Engen PA, Naqib A, Goetz CG, et al. Gut microbial metabolites in Parkinson’s disease: Association with lifestyle, disease characteristics, and treatment status. Neurobiol Dis. 2022;170:105780. 10.1016/j.nbd.2022.105780.Search in Google Scholar PubMed PubMed Central

[36] Zanelli SA, Solenski NJ, Rosenthal RE, Fiskum G. Mechanisms of ischemic neuroprotection by acetyl-L-carnitine. Ann N Y Acad Sci. 2005;1053:153–61. 10.1196/annals.1344.013.Search in Google Scholar PubMed PubMed Central

[37] Iantomasi T, Favilli F, Marraccini P, Stio M, Treves C, Quattrone A, et al. Age and GSH metabolism in rat cerebral cortex, as related to oxidative and energy parameters. Mech Ageing Dev. 1993;70:65–82. 10.1016/0047-6374(93)90060-5.Search in Google Scholar PubMed

[38] Olajide OJ, Yawson EO, Gbadamosi IT, Arogundade TT, Lambe E, Obasi K, et al. Ascorbic acid ameliorates behavioural deficits and neuropathological alterations in rat model of Alzheimer’s disease. Environ Toxicol Pharmacol. 2017;50:200–11. 10.1016/j.etap.2017.02.010.Search in Google Scholar PubMed

[39] Mu RH, Tan YZ, Fu LL, Nazmul Islam M, Hu M, Hong H, et al. 1-Methylnicotinamide attenuates lipopolysaccharide-induced cognitive deficits via targeting neuroinflammation and neuronal apoptosis. Int Immunopharmacol. 2019;77:105918. 10.1016/j.intimp.2019.105918.Search in Google Scholar PubMed

[40] Zhang C, Hu Q, Li S, Dai F, Qian W, Hewlings S, et al. A Magtein®, magnesium L-threonate, -based formula improves brain cognitive functions in healthy chinese adults. Nutrients. 2022;14:5235. 10.3390/nu14245235.Search in Google Scholar PubMed PubMed Central

[41] Angela G, Andrea T, Franca A, Antonio N, Beatrice P, Silvana P, et al. Insights about urinary hippuric and citric acid as biomarkers of fruit and vegetable intake in patients with kidney stones: The role of age and sex. Nutrition. 2018;50:1–7. 10.1016/j.nut.2017.12.006.Search in Google Scholar PubMed

[42] Shafi R, Iyer SP, Ellies LG, O’Donnell N, Marek KW, Chui D, et al. The O-GlcNAc transferase gene resides on the X chromosome and is essential for embryonic stem cell viability and mouse ontogeny. Proc Natl Acad Sci U S A. 2000;97:5735–9. 10.1073/pnas.100471497.Search in Google Scholar PubMed PubMed Central

[43] Joshi S, Saylor BT, Wang W, Peck AB, Khan SR. Apocynin-treatment reverses hyperoxaluria induced changes in NADPH oxidase system expression in rat kidneys: a transcriptional study. PLoS One. 2012;7:e47738. 10.1371/journal.pone.0047738.Search in Google Scholar PubMed PubMed Central

[44] Zhou Y, Wang J, Cao L, Shi M, Liu H, Zhao Y, et al. Fruit and vegetable consumption and cognitive disorders in older adults: a meta-analysis of observational studies. Front Nutr. 2022;9:871061. 10.3389/fnut.2022.871061.Search in Google Scholar PubMed PubMed Central

[45] Xi J, Ding D, Zhu H, Wang R, Su F, Wu W, et al. Disturbed microbial ecology in Alzheimer’s disease: evidence from the gut microbiota and fecal metabolome. BMC Microbiol. 2021;21:226. 10.1186/s12866-021-02286-z.Search in Google Scholar PubMed PubMed Central

[46] Zeisel SH. Choline: an essential nutrient for humans. Nutrition. 2000;16:669–71. 10.1016/s0899-9007(00)00349-x.Search in Google Scholar PubMed

[47] Byun MS, Choi JS, Yoo SY, Kang DH, Choi CH, Jang DP, et al. Depressive Symptoms and brain metabolite alterations in subjects at ultra-high risk for psychosis: a preliminary study. Psychiatry Investig. 2009;6:264–71. 10.4306/pi.2009.6.4.264.Search in Google Scholar PubMed PubMed Central

[48] Bowden J, Holmes MV. Meta-analysis and mendelian randomization: a review. Res Synth Methods. 2019;10:486–96. 10.1002/jrsm.1346.Search in Google Scholar PubMed PubMed Central

Received: 2025-04-09
Revised: 2025-06-02
Accepted: 2025-06-13
Published Online: 2025-08-04

© 2025 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

Articles in the same Issue

  1. Research Articles
  2. Network pharmacological analysis and in vitro testing of the rutin effects on triple-negative breast cancer
  3. Impact of diabetes on long-term survival in elderly liver cancer patients: A retrospective study
  4. Knockdown of CCNB1 alleviates high glucose-triggered trophoblast dysfunction during gestational diabetes via Wnt/β-catenin signaling pathway
  5. Risk factors for severe adverse drug reactions in hospitalized patients
  6. Analysis of the effect of ALA-PDT on macrophages in footpad model of mice infected with Fonsecaea monophora based on single-cell sequencing
  7. Development and validation of headspace gas chromatography with a flame ionization detector method for the determination of ethanol in the vitreous humor
  8. CMSP exerts anti-tumor effects on small cell lung cancer cells by inducing mitochondrial dysfunction and ferroptosis
  9. Predictive value of plasma sB7-H3 and YKL-40 in pediatric refractory Mycoplasma pneumoniae pneumonia
  10. Antiangiogenic potential of Elaeagnus umbellata extracts and molecular docking study by targeting VEGFR-2 pathway
  11. Comparison of the effectiveness of nurse-led preoperative counseling and postoperative follow-up care vs standard care for patients with gastric cancer
  12. Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis
  13. Adhered macrophages as an additional marker of cardiomyocyte injury in biopsies of patients with dilated cardiomyopathy
  14. Association between statin administration and outcome in patients with sepsis: A retrospective study
  15. Exploration of the association between estimated glucose disposal rate and osteoarthritis in middle-aged and older adults: An analysis of NHANES data from 2011 to 2018
  16. A comparative analysis of the binary and multiclass classified chest X-ray images of pneumonia and COVID-19 with ML and DL models
  17. Lysophosphatidic acid 2 alleviates deep vein thrombosis via protective endothelial barrier function
  18. Transcription factor A, mitochondrial promotes lymph node metastasis and lymphangiogenesis in epithelial ovarian carcinoma
  19. Serum PM20D1 levels are associated with nutritional status and inflammatory factors in gastric cancer patients undergoing early enteral nutrition
  20. Hydromorphone reduced the incidence of emergence agitation after adenotonsillectomy in children with obstructive sleep apnea: A randomized, double-blind study
  21. Vitamin D replacement therapy may regulate sleep habits in patients with restless leg syndrome
  22. The first-line antihypertensive nitrendipine potentiated the therapeutic effect of oxaliplatin by downregulating CACNA1D in colorectal cancer
  23. Health literacy and health-related quality of life: The mediating role of irrational happiness
  24. Modulatory effects of Lycium barbarum polysaccharide on bone cell dynamics in osteoporosis
  25. Mechanism research on inhibition of gastric cancer in vitro by the extract of Pinellia ternata based on network pharmacology and cellular metabolomics
  26. Examination of the causal role of immune cells in non-alcoholic fatty liver disease by a bidirectional Mendelian randomization study
  27. Clinical analysis of ten cases of HIV infection combined with acute leukemia
  28. Investigating the cardioprotective potential of quercetin against tacrolimus-induced cardiotoxicity in Wistar rats: A mechanistic insights
  29. Clinical observation of probiotics combined with mesalazine and Yiyi Baitouweng Decoction retention enema in treating mild-to-moderate ulcerative colitis
  30. Diagnostic value of ratio of blood inflammation to coagulation markers in periprosthetic joint infection
  31. Sex-specific associations of sex hormone binding globulin and risk of bladder cancer
  32. Core muscle strength and stability-oriented breathing training reduces inter-recti distance in postpartum women
  33. The ERAS nursing care strategy for patients undergoing transsphenoidal endoscopic pituitary tumor resection: A randomized blinded controlled trial
  34. The serum IL-17A levels in patients with traumatic bowel rupture post-surgery and its predictive value for patient prognosis
  35. Impact of Kolb’s experiential learning theory-based nursing on caregiver burden and psychological state of caregivers of dementia patients
  36. Analysis of serum NLR combined with intraoperative margin condition to predict the prognosis of cervical HSIL patients undergoing LEEP surgery
  37. Commiphora gileadensis ameliorate infertility and erectile dysfunction in diabetic male mice
  38. The correlation between epithelial–mesenchymal transition classification and MMP2 expression of circulating tumor cells and prognosis of advanced or metastatic nasopharyngeal carcinoma
  39. Tetrahydropalmatine improves mitochondrial function in vascular smooth muscle cells of atherosclerosis in vitro by inhibiting Ras homolog gene family A/Rho-associated protein kinase-1 signaling pathway
  40. A cross-sectional study: Relationship between serum oxidative stress levels and arteriovenous fistula maturation in maintenance dialysis patients
  41. A comparative analysis of the impact of repeated administration of flavan 3-ol on brown, subcutaneous, and visceral adipose tissue
  42. Identifying early screening factors for depression in middle-aged and older adults: A cohort study
  43. Perform tumor-specific survival analysis for Merkel cell carcinoma patients undergoing surgical resection based on the SEER database by constructing a nomogram chart
  44. Unveiling the role of CXCL10 in pancreatic cancer progression: A novel prognostic indicator
  45. High-dose preoperative intraperitoneal erythropoietin and intravenous methylprednisolone in acute traumatic spinal cord injuries following decompression surgeries
  46. RAB39B: A novel biomarker for acute myeloid leukemia identified via multi-omics and functional validation
  47. Impact of peripheral conditioning on reperfusion injury following primary percutaneous coronary intervention in diabetic and non-diabetic STEMI patients
  48. Clinical efficacy of azacitidine in the treatment of middle- and high-risk myelodysplastic syndrome in middle-aged and elderly patients: A retrospective study
  49. The effect of ambulatory blood pressure load on mitral regurgitation in continuous ambulatory peritoneal dialysis patients
  50. Expression and clinical significance of ITGA3 in breast cancer
  51. Single-nucleus RNA sequencing reveals ARHGAP28 expression of podocytes as a biomarker in human diabetic nephropathy
  52. rSIG combined with NLR in the prognostic assessment of patients with multiple injuries
  53. Toxic metals and metalloids in collagen supplements of fish and jellyfish origin: Risk assessment for daily intake
  54. Exploring causal relationship between 41 inflammatory cytokines and marginal zone lymphoma: A bidirectional Mendelian randomization study
  55. Gender beliefs and legitimization of dating violence in adolescents
  56. Effect of serum IL-6, CRP, and MMP-9 levels on the efficacy of modified preperitoneal Kugel repair in patients with inguinal hernia
  57. Effect of smoking and smoking cessation on hematological parameters in polycythemic patients
  58. Pathogen surveillance and risk factors for pulmonary infection in patients with lung cancer: A retrospective single-center study
  59. Necroptosis of hippocampal neurons in paclitaxel chemotherapy-induced cognitive impairment mediates microglial activation via TLR4/MyD88 signaling pathway
  60. Celastrol suppresses neovascularization in rat aortic vascular endothelial cells stimulated by inflammatory tenocytes via modulating the NLRP3 pathway
  61. Cord-lamina angle and foraminal diameter as key predictors of C5 palsy after anterior cervical decompression and fusion surgery
  62. GATA1: A key biomarker for predicting the prognosis of patients with diffuse large B-cell lymphoma
  63. Influencing factors of false lumen thrombosis in type B aortic dissection: A single-center retrospective study
  64. MZB1 regulates the immune microenvironment and inhibits ovarian cancer cell migration
  65. Integrating experimental and network pharmacology to explore the pharmacological mechanisms of Dioscin against glioblastoma
  66. Trends in research on preterm birth in twin pregnancy based on bibliometrics
  67. Four-week IgE/baseline IgE ratio combined with tryptase predicts clinical outcome in omalizumab-treated children with moderate-to-severe asthma
  68. Single-cell transcriptomic analysis identifies a stress response Schwann cell subtype
  69. Acute pancreatitis risk in the diagnosis and management of inflammatory bowel disease: A critical focus
  70. Effect of subclinical esketamine on NLRP3 and cognitive dysfunction in elderly ischemic stroke patients
  71. Interleukin-37 mediates the anti-oral tumor activity in oral cancer through STAT3
  72. CA199 and CEA expression levels, and minimally invasive postoperative prognosis analysis in esophageal squamous carcinoma patients
  73. Efficacy of a novel drainage catheter in the treatment of CSF leak after posterior spine surgery: A retrospective cohort study
  74. Comprehensive biomedicine assessment of Apteranthes tuberculata extracts: Phytochemical analysis and multifaceted pharmacological evaluation in animal models
  75. Relation of time in range to severity of coronary artery disease in patients with type 2 diabetes: A cross-sectional study
  76. Dopamine attenuates ethanol-induced neuronal apoptosis by stimulating electrical activity in the developing rat retina
  77. Correlation between albumin levels during the third trimester and the risk of postpartum levator ani muscle rupture
  78. Factors associated with maternal attention and distraction during breastfeeding and childcare: A cross-sectional study in the west of Iran
  79. Mechanisms of hesperetin in treating metabolic dysfunction-associated steatosis liver disease via network pharmacology and in vitro experiments
  80. The law on oncological oblivion in the Italian and European context: How to best uphold the cancer patients’ rights to privacy and self-determination?
  81. The prognostic value of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and prognostic nutritional index for survival in patients with colorectal cancer
  82. Factors affecting the measurements of peripheral oxygen saturation values in healthy young adults
  83. Comparison and correlations between findings of hysteroscopy and vaginal color Doppler ultrasonography for detection of uterine abnormalities in patients with recurrent implantation failure
  84. The effects of different types of RAGT on balance function in stroke patients with low levels of independent walking in a convalescent rehabilitation hospital
  85. Causal relationship between asthma and ankylosing spondylitis: A bidirectional two-sample univariable and multivariable Mendelian randomization study
  86. Correlations of health literacy with individuals’ understanding and use of medications in Southern Taiwan
  87. Correlation of serum calprotectin with outcome of acute cerebral infarction
  88. Comparison of computed tomography and guided bronchoscopy in the diagnosis of pulmonary nodules: A systematic review and meta-analysis
  89. Curdione protects vascular endothelial cells and atherosclerosis via the regulation of DNMT1-mediated ERBB4 promoter methylation
  90. The identification of novel missense variant in ChAT gene in a patient with gestational diabetes denotes plausible genetic association
  91. Molecular genotyping of multi-system rare blood types in foreign blood donors based on DNA sequencing and its clinical significance
  92. Exploring the role of succinyl carnitine in the association between CD39⁺ CD4⁺ T cell and ulcerative colitis: A Mendelian randomization study
  93. Dexmedetomidine suppresses microglial activation in postoperative cognitive dysfunction via the mmu-miRNA-125/TRAF6 signaling axis
  94. Analysis of serum metabolomics in patients with different types of chronic heart failure
  95. Diagnostic value of hematological parameters in the early diagnosis of acute cholecystitis
  96. Pachymaran alleviates fat accumulation, hepatocyte degeneration, and injury in mice with nonalcoholic fatty liver disease
  97. Decrease in CD4 and CD8 lymphocytes are predictors of severe clinical picture and unfavorable outcome of the disease in patients with COVID-19
  98. METTL3 blocked the progression of diabetic retinopathy through m6A-modified SOX2
  99. The predictive significance of anti-RO-52 antibody in patients with interstitial pneumonia after treatment of malignant tumors
  100. Exploring cerebrospinal fluid metabolites, cognitive function, and brain atrophy: Insights from Mendelian randomization
  101. Development and validation of potential molecular subtypes and signatures of ocular sarcoidosis based on autophagy-related gene analysis
  102. Widespread venous thrombosis: Unveiling a complex case of Behçet’s disease with a literature perspective
  103. Uterine fibroid embolization: An analysis of clinical outcomes and impact on patients’ quality of life
  104. Discovery of lipid metabolism-related diagnostic biomarkers and construction of diagnostic model in steroid-induced osteonecrosis of femoral head
  105. Serum-derived exomiR-188-3p is a promising novel biomarker for early-stage ovarian cancer
  106. Enhancing chronic back pain management: A comparative study of ultrasound–MRI fusion guidance for paravertebral nerve block
  107. Peptide CCAT1-70aa promotes hepatocellular carcinoma proliferation and invasion via the MAPK/ERK pathway
  108. Electroacupuncture-induced reduction of myocardial ischemia–reperfusion injury via FTO-dependent m6A methylation modulation
  109. Hemorrhoids and cardiovascular disease: A bidirectional Mendelian randomization study
  110. Cell-free adipose extract inhibits hypertrophic scar formation through collagen remodeling and antiangiogenesis
  111. HALP score in Demodex blepharitis: A case–control study
  112. Assessment of SOX2 performance as a marker for circulating cancer stem-like cells (CCSCs) identification in advanced breast cancer patients using CytoTrack system
  113. Risk and prognosis for brain metastasis in primary metastatic cervical cancer patients: A population-based study
  114. Comparison of the two intestinal anastomosis methods in pediatric patients
  115. Factors influencing hematological toxicity and adverse effects of perioperative hyperthermic intraperitoneal vs intraperitoneal chemotherapy in gastrointestinal cancer
  116. Endotoxin tolerance inhibits NLRP3 inflammasome activation in macrophages of septic mice by restoring autophagic flux through TRIM26
  117. Lateral transperitoneal laparoscopic adrenalectomy: A single-centre experience of 21 procedures
  118. Petunidin attenuates lipopolysaccharide-induced retinal microglia inflammatory response in diabetic retinopathy by targeting OGT/NF-κB/LCN2 axis
  119. Procalcitonin and C-reactive protein as biomarkers for diagnosing and assessing the severity of acute cholecystitis
  120. Factors determining the number of sessions in successful extracorporeal shock wave lithotripsy patients
  121. Development of a nomogram for predicting cancer-specific survival in patients with renal pelvic cancer following surgery
  122. Inhibition of ATG7 promotes orthodontic tooth movement by regulating the RANKL/OPG ratio under compression force
  123. A machine learning-based prognostic model integrating mRNA stemness index, hypoxia, and glycolysis‑related biomarkers for colorectal cancer
  124. Glutathione attenuates sepsis-associated encephalopathy via dual modulation of NF-κB and PKA/CREB pathways
  125. FAHD1 prevents neuronal ferroptosis by modulating R-loop and the cGAS–STING pathway
  126. Association of placenta weight and morphology with term low birth weight: A case–control study
  127. Investigation of the pathogenic variants induced Sjogren’s syndrome in Turkish population
  128. Nucleotide metabolic abnormalities in post-COVID-19 condition and type 2 diabetes mellitus patients and their association with endocrine dysfunction
  129. TGF-β–Smad2/3 signaling in high-altitude pulmonary hypertension in rats: Role and mechanisms via macrophage M2 polarization
  130. Ultrasound-guided unilateral versus bilateral erector spinae plane block for postoperative analgesia of patients undergoing laparoscopic cholecystectomy
  131. Profiling gut microbiome dynamics in subacute thyroiditis: Implications for pathogenesis, diagnosis, and treatment
  132. Delta neutrophil index, CRP/albumin ratio, procalcitonin, immature granulocytes, and HALP score in acute appendicitis: Best performing biomarker?
  133. Anticancer activity mechanism of novelly synthesized and characterized benzofuran ring-linked 3-nitrophenyl chalcone derivative on colon cancer cells
  134. H2valdien3 arrests the cell cycle and induces apoptosis of gastric cancer
  135. Prognostic relevance of PRSS2 and its immune correlates in papillary thyroid carcinoma
  136. Association of SGLT2 inhibition with psychiatric disorders: A Mendelian randomization study
  137. Motivational interviewing for alcohol use reduction in Thai patients
  138. Luteolin alleviates oxygen-glucose deprivation/reoxygenation-induced neuron injury by regulating NLRP3/IL-1β signaling
  139. Polyphyllin II inhibits thyroid cancer cell growth by simultaneously inhibiting glycolysis and oxidative phosphorylation
  140. Relationship between the expression of copper death promoting factor SLC31A1 in papillary thyroid carcinoma and clinicopathological indicators and prognosis
  141. CSF2 polarized neutrophils and invaded renal cancer cells in vitro influence
  142. Proton pump inhibitors-induced thrombocytopenia: A systematic literature analysis of case reports
  143. The current status and influence factors of research ability among community nurses: A sequential qualitative–quantitative study
  144. OKAIN: A comprehensive oncology knowledge base for the interpretation of clinically actionable alterations
  145. The relationship between serum CA50, CA242, and SAA levels and clinical pathological characteristics and prognosis in patients with pancreatic cancer
  146. Identification and external validation of a prognostic signature based on hypoxia–glycolysis-related genes for kidney renal clear cell carcinoma
  147. Engineered RBC-derived nanovesicles functionalized with tumor-targeting ligands: A comparative study on breast cancer targeting efficiency and biocompatibility
  148. Relationship of resting echocardiography combined with serum micronutrients to the severity of low-gradient severe aortic stenosis
  149. Effect of vibration on pain during subcutaneous heparin injection: A randomized, single-blind, placebo-controlled trial
  150. The diagnostic performance of machine learning-based FFRCT for coronary artery disease: A meta-analysis
  151. Comparing biofeedback device vs diaphragmatic breathing for bloating relief: A randomized controlled trial
  152. Serum uric acid to albumin ratio and C-reactive protein as predictive biomarkers for chronic total occlusion and coronary collateral circulation quality
  153. Multiple organ scoring systems for predicting in-hospital mortality of sepsis patients in the intensive care unit
  154. Single-cell RNA sequencing data analysis of the inner ear in gentamicin-treated mice via intraperitoneal injection
  155. Review Articles
  156. The effects of enhanced external counter-pulsation on post-acute sequelae of COVID-19: A narrative review
  157. Diabetes-related cognitive impairment: Mechanisms, symptoms, and treatments
  158. Microscopic changes and gross morphology of placenta in women affected by gestational diabetes mellitus in dietary treatment: A systematic review
  159. Review of mechanisms and frontier applications in IL-17A-induced hypertension
  160. Research progress on the correlation between islet amyloid peptides and type 2 diabetes mellitus
  161. The safety and efficacy of BCG combined with mitomycin C compared with BCG monotherapy in patients with non-muscle-invasive bladder cancer: A systematic review and meta-analysis
  162. The application of augmented reality in robotic general surgery: A mini-review
  163. The effect of Greek mountain tea extract and wheat germ extract on peripheral blood flow and eicosanoid metabolism in mammals
  164. Neurogasobiology of migraine: Carbon monoxide, hydrogen sulfide, and nitric oxide as emerging pathophysiological trinacrium relevant to nociception regulation
  165. Plant polyphenols, terpenes, and terpenoids in oral health
  166. Laboratory medicine between technological innovation, rights safeguarding, and patient safety: A bioethical perspective
  167. End-of-life in cancer patients: Medicolegal implications and ethical challenges in Europe
  168. The maternal factors during pregnancy for intrauterine growth retardation: An umbrella review
  169. Intra-abdominal hypertension/abdominal compartment syndrome of pediatric patients in critical care settings
  170. PI3K/Akt pathway and neuroinflammation in sepsis-associated encephalopathy
  171. Screening of Group B Streptococcus in pregnancy: A systematic review for the laboratory detection
  172. Giant borderline ovarian tumours – review of the literature
  173. Leveraging artificial intelligence for collaborative care planning: Innovations and impacts in shared decision-making – A systematic review
  174. Cholera epidemiology analysis through the experience of the 1973 Naples epidemic
  175. Risk factors of frailty/sarcopenia in community older adults: Meta-analysis
  176. Supplement strategies for infertility in overweight women: Evidence and legal insights
  177. Scurvy, a not obsolete disorder: Clinical report in eight young children and literature review
  178. A meta-analysis of the effects of DBS on cognitive function in patients with advanced PD
  179. Protective role of selenium in sepsis: Mechanisms and potential therapeutic strategies
  180. Strategies for hyperkalemia management in dialysis patients: A systematic review
  181. C-reactive protein-to-albumin ratio in peripheral artery disease
  182. Case Reports
  183. Delayed graft function after renal transplantation
  184. Semaglutide treatment for type 2 diabetes in a patient with chronic myeloid leukemia: A case report and review of the literature
  185. Diverse electrophysiological demyelinating features in a late-onset glycogen storage disease type IIIa case
  186. Giant right atrial hemangioma presenting with ascites: A case report
  187. Laser excision of a large granular cell tumor of the vocal cord with subglottic extension: A case report
  188. EsoFLIP-assisted dilation for dysphagia in systemic sclerosis: Highlighting the role of multimodal esophageal evaluation
  189. Molecular hydrogen-rhodiola as an adjuvant therapy for ischemic stroke in internal carotid artery occlusion: A case report
  190. Coronary artery anomalies: A case of the “malignant” left coronary artery and its surgical management
  191. Rapid Communication
  192. Biological properties of valve materials using RGD and EC
  193. A single oral administration of flavanols enhances short-term memory in mice along with increased brain-derived neurotrophic factor
  194. Letter to the Editor
  195. Role of enhanced external counterpulsation in long COVID
  196. Expression of Concern
  197. Expression of concern “A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma”
  198. Expression of concern “Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway”
  199. Expression of concern “circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8”
  200. Corrigendum
  201. Corrigendum to “Empagliflozin improves aortic injury in obese mice by regulating fatty acid metabolism”
  202. Corrigendum to “Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis”
  203. Corrigendum to “The progress of autoimmune hepatitis research and future challenges”
  204. Retraction
  205. Retraction of “miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway”
  206. Retraction of: “LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through downregulating SP-A by sponging to miR-424”
  207. Retraction of: “SCARA5 inhibits oral squamous cell carcinoma via inactivating the STAT3 and PI3K/AKT signaling pathways”
  208. Special Issue Advancements in oncology: bridging clinical and experimental research - Part II
  209. Unveiling novel biomarkers for platinum chemoresistance in ovarian cancer
  210. Lathyrol affects the expression of AR and PSA and inhibits the malignant behavior of RCC cells
  211. The era of increasing cancer survivorship: Trends in fertility preservation, medico-legal implications, and ethical challenges
  212. Bone scintigraphy and positron emission tomography in the early diagnosis of MRONJ
  213. Meta-analysis of clinical efficacy and safety of immunotherapy combined with chemotherapy in non-small cell lung cancer
  214. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part IV
  215. Exploration of mRNA-modifying METTL3 oncogene as momentous prognostic biomarker responsible for colorectal cancer development
  216. Special Issue The evolving saga of RNAs from bench to bedside - Part III
  217. Interaction and verification of ferroptosis-related RNAs Rela and Stat3 in promoting sepsis-associated acute kidney injury
  218. The mRNA MOXD1: Link to oxidative stress and prognostic significance in gastric cancer
  219. Special Issue Exploring the biological mechanism of human diseases based on MultiOmics Technology - Part II
  220. Dynamic changes in lactate-related genes in microglia and their role in immune cell interactions after ischemic stroke
  221. A prognostic model correlated with fatty acid metabolism in Ewing’s sarcoma based on bioinformatics analysis
  222. Red cell distribution width predicts early kidney injury: A NHANES cross-sectional study
  223. Special Issue Diabetes mellitus: pathophysiology, complications & treatment
  224. Nutritional risk assessment and nutritional support in children with congenital diabetes during surgery
  225. Correlation of the differential expressions of RANK, RANKL, and OPG with obesity in the elderly population in Xinjiang
  226. A discussion on the application of fluorescence micro-optical sectioning tomography in the research of cognitive dysfunction in diabetes
  227. A review of brain research on T2DM-related cognitive dysfunction
  228. Metformin and estrogen modulation in LABC with T2DM: A 36-month randomized trial
  229. Special Issue Innovative Biomarker Discovery and Precision Medicine in Cancer Diagnostics
  230. CircASH1L-mediated tumor progression in triple-negative breast cancer: PI3K/AKT pathway mechanisms
https://doi.org/10.1515/med-2025-1237
Keywords for this article
cerebrospinal fluid; metabolomics; cognition; brain atrophy; Mendelian randomization
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Articles
  2. Network pharmacological analysis and in vitro testing of the rutin effects on triple-negative breast cancer
  3. Impact of diabetes on long-term survival in elderly liver cancer patients: A retrospective study
  4. Knockdown of CCNB1 alleviates high glucose-triggered trophoblast dysfunction during gestational diabetes via Wnt/β-catenin signaling pathway
  5. Risk factors for severe adverse drug reactions in hospitalized patients
  6. Analysis of the effect of ALA-PDT on macrophages in footpad model of mice infected with Fonsecaea monophora based on single-cell sequencing
  7. Development and validation of headspace gas chromatography with a flame ionization detector method for the determination of ethanol in the vitreous humor
  8. CMSP exerts anti-tumor effects on small cell lung cancer cells by inducing mitochondrial dysfunction and ferroptosis
  9. Predictive value of plasma sB7-H3 and YKL-40 in pediatric refractory Mycoplasma pneumoniae pneumonia
  10. Antiangiogenic potential of Elaeagnus umbellata extracts and molecular docking study by targeting VEGFR-2 pathway
  11. Comparison of the effectiveness of nurse-led preoperative counseling and postoperative follow-up care vs standard care for patients with gastric cancer
  12. Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis
  13. Adhered macrophages as an additional marker of cardiomyocyte injury in biopsies of patients with dilated cardiomyopathy
  14. Association between statin administration and outcome in patients with sepsis: A retrospective study
  15. Exploration of the association between estimated glucose disposal rate and osteoarthritis in middle-aged and older adults: An analysis of NHANES data from 2011 to 2018
  16. A comparative analysis of the binary and multiclass classified chest X-ray images of pneumonia and COVID-19 with ML and DL models
  17. Lysophosphatidic acid 2 alleviates deep vein thrombosis via protective endothelial barrier function
  18. Transcription factor A, mitochondrial promotes lymph node metastasis and lymphangiogenesis in epithelial ovarian carcinoma
  19. Serum PM20D1 levels are associated with nutritional status and inflammatory factors in gastric cancer patients undergoing early enteral nutrition
  20. Hydromorphone reduced the incidence of emergence agitation after adenotonsillectomy in children with obstructive sleep apnea: A randomized, double-blind study
  21. Vitamin D replacement therapy may regulate sleep habits in patients with restless leg syndrome
  22. The first-line antihypertensive nitrendipine potentiated the therapeutic effect of oxaliplatin by downregulating CACNA1D in colorectal cancer
  23. Health literacy and health-related quality of life: The mediating role of irrational happiness
  24. Modulatory effects of Lycium barbarum polysaccharide on bone cell dynamics in osteoporosis
  25. Mechanism research on inhibition of gastric cancer in vitro by the extract of Pinellia ternata based on network pharmacology and cellular metabolomics
  26. Examination of the causal role of immune cells in non-alcoholic fatty liver disease by a bidirectional Mendelian randomization study
  27. Clinical analysis of ten cases of HIV infection combined with acute leukemia
  28. Investigating the cardioprotective potential of quercetin against tacrolimus-induced cardiotoxicity in Wistar rats: A mechanistic insights
  29. Clinical observation of probiotics combined with mesalazine and Yiyi Baitouweng Decoction retention enema in treating mild-to-moderate ulcerative colitis
  30. Diagnostic value of ratio of blood inflammation to coagulation markers in periprosthetic joint infection
  31. Sex-specific associations of sex hormone binding globulin and risk of bladder cancer
  32. Core muscle strength and stability-oriented breathing training reduces inter-recti distance in postpartum women
  33. The ERAS nursing care strategy for patients undergoing transsphenoidal endoscopic pituitary tumor resection: A randomized blinded controlled trial
  34. The serum IL-17A levels in patients with traumatic bowel rupture post-surgery and its predictive value for patient prognosis
  35. Impact of Kolb’s experiential learning theory-based nursing on caregiver burden and psychological state of caregivers of dementia patients
  36. Analysis of serum NLR combined with intraoperative margin condition to predict the prognosis of cervical HSIL patients undergoing LEEP surgery
  37. Commiphora gileadensis ameliorate infertility and erectile dysfunction in diabetic male mice
  38. The correlation between epithelial–mesenchymal transition classification and MMP2 expression of circulating tumor cells and prognosis of advanced or metastatic nasopharyngeal carcinoma
  39. Tetrahydropalmatine improves mitochondrial function in vascular smooth muscle cells of atherosclerosis in vitro by inhibiting Ras homolog gene family A/Rho-associated protein kinase-1 signaling pathway
  40. A cross-sectional study: Relationship between serum oxidative stress levels and arteriovenous fistula maturation in maintenance dialysis patients
  41. A comparative analysis of the impact of repeated administration of flavan 3-ol on brown, subcutaneous, and visceral adipose tissue
  42. Identifying early screening factors for depression in middle-aged and older adults: A cohort study
  43. Perform tumor-specific survival analysis for Merkel cell carcinoma patients undergoing surgical resection based on the SEER database by constructing a nomogram chart
  44. Unveiling the role of CXCL10 in pancreatic cancer progression: A novel prognostic indicator
  45. High-dose preoperative intraperitoneal erythropoietin and intravenous methylprednisolone in acute traumatic spinal cord injuries following decompression surgeries
  46. RAB39B: A novel biomarker for acute myeloid leukemia identified via multi-omics and functional validation
  47. Impact of peripheral conditioning on reperfusion injury following primary percutaneous coronary intervention in diabetic and non-diabetic STEMI patients
  48. Clinical efficacy of azacitidine in the treatment of middle- and high-risk myelodysplastic syndrome in middle-aged and elderly patients: A retrospective study
  49. The effect of ambulatory blood pressure load on mitral regurgitation in continuous ambulatory peritoneal dialysis patients
  50. Expression and clinical significance of ITGA3 in breast cancer
  51. Single-nucleus RNA sequencing reveals ARHGAP28 expression of podocytes as a biomarker in human diabetic nephropathy
  52. rSIG combined with NLR in the prognostic assessment of patients with multiple injuries
  53. Toxic metals and metalloids in collagen supplements of fish and jellyfish origin: Risk assessment for daily intake
  54. Exploring causal relationship between 41 inflammatory cytokines and marginal zone lymphoma: A bidirectional Mendelian randomization study
  55. Gender beliefs and legitimization of dating violence in adolescents
  56. Effect of serum IL-6, CRP, and MMP-9 levels on the efficacy of modified preperitoneal Kugel repair in patients with inguinal hernia
  57. Effect of smoking and smoking cessation on hematological parameters in polycythemic patients
  58. Pathogen surveillance and risk factors for pulmonary infection in patients with lung cancer: A retrospective single-center study
  59. Necroptosis of hippocampal neurons in paclitaxel chemotherapy-induced cognitive impairment mediates microglial activation via TLR4/MyD88 signaling pathway
  60. Celastrol suppresses neovascularization in rat aortic vascular endothelial cells stimulated by inflammatory tenocytes via modulating the NLRP3 pathway
  61. Cord-lamina angle and foraminal diameter as key predictors of C5 palsy after anterior cervical decompression and fusion surgery
  62. GATA1: A key biomarker for predicting the prognosis of patients with diffuse large B-cell lymphoma
  63. Influencing factors of false lumen thrombosis in type B aortic dissection: A single-center retrospective study
  64. MZB1 regulates the immune microenvironment and inhibits ovarian cancer cell migration
  65. Integrating experimental and network pharmacology to explore the pharmacological mechanisms of Dioscin against glioblastoma
  66. Trends in research on preterm birth in twin pregnancy based on bibliometrics
  67. Four-week IgE/baseline IgE ratio combined with tryptase predicts clinical outcome in omalizumab-treated children with moderate-to-severe asthma
  68. Single-cell transcriptomic analysis identifies a stress response Schwann cell subtype
  69. Acute pancreatitis risk in the diagnosis and management of inflammatory bowel disease: A critical focus
  70. Effect of subclinical esketamine on NLRP3 and cognitive dysfunction in elderly ischemic stroke patients
  71. Interleukin-37 mediates the anti-oral tumor activity in oral cancer through STAT3
  72. CA199 and CEA expression levels, and minimally invasive postoperative prognosis analysis in esophageal squamous carcinoma patients
  73. Efficacy of a novel drainage catheter in the treatment of CSF leak after posterior spine surgery: A retrospective cohort study
  74. Comprehensive biomedicine assessment of Apteranthes tuberculata extracts: Phytochemical analysis and multifaceted pharmacological evaluation in animal models
  75. Relation of time in range to severity of coronary artery disease in patients with type 2 diabetes: A cross-sectional study
  76. Dopamine attenuates ethanol-induced neuronal apoptosis by stimulating electrical activity in the developing rat retina
  77. Correlation between albumin levels during the third trimester and the risk of postpartum levator ani muscle rupture
  78. Factors associated with maternal attention and distraction during breastfeeding and childcare: A cross-sectional study in the west of Iran
  79. Mechanisms of hesperetin in treating metabolic dysfunction-associated steatosis liver disease via network pharmacology and in vitro experiments
  80. The law on oncological oblivion in the Italian and European context: How to best uphold the cancer patients’ rights to privacy and self-determination?
  81. The prognostic value of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and prognostic nutritional index for survival in patients with colorectal cancer
  82. Factors affecting the measurements of peripheral oxygen saturation values in healthy young adults
  83. Comparison and correlations between findings of hysteroscopy and vaginal color Doppler ultrasonography for detection of uterine abnormalities in patients with recurrent implantation failure
  84. The effects of different types of RAGT on balance function in stroke patients with low levels of independent walking in a convalescent rehabilitation hospital
  85. Causal relationship between asthma and ankylosing spondylitis: A bidirectional two-sample univariable and multivariable Mendelian randomization study
  86. Correlations of health literacy with individuals’ understanding and use of medications in Southern Taiwan
  87. Correlation of serum calprotectin with outcome of acute cerebral infarction
  88. Comparison of computed tomography and guided bronchoscopy in the diagnosis of pulmonary nodules: A systematic review and meta-analysis
  89. Curdione protects vascular endothelial cells and atherosclerosis via the regulation of DNMT1-mediated ERBB4 promoter methylation
  90. The identification of novel missense variant in ChAT gene in a patient with gestational diabetes denotes plausible genetic association
  91. Molecular genotyping of multi-system rare blood types in foreign blood donors based on DNA sequencing and its clinical significance
  92. Exploring the role of succinyl carnitine in the association between CD39⁺ CD4⁺ T cell and ulcerative colitis: A Mendelian randomization study
  93. Dexmedetomidine suppresses microglial activation in postoperative cognitive dysfunction via the mmu-miRNA-125/TRAF6 signaling axis
  94. Analysis of serum metabolomics in patients with different types of chronic heart failure
  95. Diagnostic value of hematological parameters in the early diagnosis of acute cholecystitis
  96. Pachymaran alleviates fat accumulation, hepatocyte degeneration, and injury in mice with nonalcoholic fatty liver disease
  97. Decrease in CD4 and CD8 lymphocytes are predictors of severe clinical picture and unfavorable outcome of the disease in patients with COVID-19
  98. METTL3 blocked the progression of diabetic retinopathy through m6A-modified SOX2
  99. The predictive significance of anti-RO-52 antibody in patients with interstitial pneumonia after treatment of malignant tumors
  100. Exploring cerebrospinal fluid metabolites, cognitive function, and brain atrophy: Insights from Mendelian randomization
  101. Development and validation of potential molecular subtypes and signatures of ocular sarcoidosis based on autophagy-related gene analysis
  102. Widespread venous thrombosis: Unveiling a complex case of Behçet’s disease with a literature perspective
  103. Uterine fibroid embolization: An analysis of clinical outcomes and impact on patients’ quality of life
  104. Discovery of lipid metabolism-related diagnostic biomarkers and construction of diagnostic model in steroid-induced osteonecrosis of femoral head
  105. Serum-derived exomiR-188-3p is a promising novel biomarker for early-stage ovarian cancer
  106. Enhancing chronic back pain management: A comparative study of ultrasound–MRI fusion guidance for paravertebral nerve block
  107. Peptide CCAT1-70aa promotes hepatocellular carcinoma proliferation and invasion via the MAPK/ERK pathway
  108. Electroacupuncture-induced reduction of myocardial ischemia–reperfusion injury via FTO-dependent m6A methylation modulation
  109. Hemorrhoids and cardiovascular disease: A bidirectional Mendelian randomization study
  110. Cell-free adipose extract inhibits hypertrophic scar formation through collagen remodeling and antiangiogenesis
  111. HALP score in Demodex blepharitis: A case–control study
  112. Assessment of SOX2 performance as a marker for circulating cancer stem-like cells (CCSCs) identification in advanced breast cancer patients using CytoTrack system
  113. Risk and prognosis for brain metastasis in primary metastatic cervical cancer patients: A population-based study
  114. Comparison of the two intestinal anastomosis methods in pediatric patients
  115. Factors influencing hematological toxicity and adverse effects of perioperative hyperthermic intraperitoneal vs intraperitoneal chemotherapy in gastrointestinal cancer
  116. Endotoxin tolerance inhibits NLRP3 inflammasome activation in macrophages of septic mice by restoring autophagic flux through TRIM26
  117. Lateral transperitoneal laparoscopic adrenalectomy: A single-centre experience of 21 procedures
  118. Petunidin attenuates lipopolysaccharide-induced retinal microglia inflammatory response in diabetic retinopathy by targeting OGT/NF-κB/LCN2 axis
  119. Procalcitonin and C-reactive protein as biomarkers for diagnosing and assessing the severity of acute cholecystitis
  120. Factors determining the number of sessions in successful extracorporeal shock wave lithotripsy patients
  121. Development of a nomogram for predicting cancer-specific survival in patients with renal pelvic cancer following surgery
  122. Inhibition of ATG7 promotes orthodontic tooth movement by regulating the RANKL/OPG ratio under compression force
  123. A machine learning-based prognostic model integrating mRNA stemness index, hypoxia, and glycolysis‑related biomarkers for colorectal cancer
  124. Glutathione attenuates sepsis-associated encephalopathy via dual modulation of NF-κB and PKA/CREB pathways
  125. FAHD1 prevents neuronal ferroptosis by modulating R-loop and the cGAS–STING pathway
  126. Association of placenta weight and morphology with term low birth weight: A case–control study
  127. Investigation of the pathogenic variants induced Sjogren’s syndrome in Turkish population
  128. Nucleotide metabolic abnormalities in post-COVID-19 condition and type 2 diabetes mellitus patients and their association with endocrine dysfunction
  129. TGF-β–Smad2/3 signaling in high-altitude pulmonary hypertension in rats: Role and mechanisms via macrophage M2 polarization
  130. Ultrasound-guided unilateral versus bilateral erector spinae plane block for postoperative analgesia of patients undergoing laparoscopic cholecystectomy
  131. Profiling gut microbiome dynamics in subacute thyroiditis: Implications for pathogenesis, diagnosis, and treatment
  132. Delta neutrophil index, CRP/albumin ratio, procalcitonin, immature granulocytes, and HALP score in acute appendicitis: Best performing biomarker?
  133. Anticancer activity mechanism of novelly synthesized and characterized benzofuran ring-linked 3-nitrophenyl chalcone derivative on colon cancer cells
  134. H2valdien3 arrests the cell cycle and induces apoptosis of gastric cancer
  135. Prognostic relevance of PRSS2 and its immune correlates in papillary thyroid carcinoma
  136. Association of SGLT2 inhibition with psychiatric disorders: A Mendelian randomization study
  137. Motivational interviewing for alcohol use reduction in Thai patients
  138. Luteolin alleviates oxygen-glucose deprivation/reoxygenation-induced neuron injury by regulating NLRP3/IL-1β signaling
  139. Polyphyllin II inhibits thyroid cancer cell growth by simultaneously inhibiting glycolysis and oxidative phosphorylation
  140. Relationship between the expression of copper death promoting factor SLC31A1 in papillary thyroid carcinoma and clinicopathological indicators and prognosis
  141. CSF2 polarized neutrophils and invaded renal cancer cells in vitro influence
  142. Proton pump inhibitors-induced thrombocytopenia: A systematic literature analysis of case reports
  143. The current status and influence factors of research ability among community nurses: A sequential qualitative–quantitative study
  144. OKAIN: A comprehensive oncology knowledge base for the interpretation of clinically actionable alterations
  145. The relationship between serum CA50, CA242, and SAA levels and clinical pathological characteristics and prognosis in patients with pancreatic cancer
  146. Identification and external validation of a prognostic signature based on hypoxia–glycolysis-related genes for kidney renal clear cell carcinoma
  147. Engineered RBC-derived nanovesicles functionalized with tumor-targeting ligands: A comparative study on breast cancer targeting efficiency and biocompatibility
  148. Relationship of resting echocardiography combined with serum micronutrients to the severity of low-gradient severe aortic stenosis
  149. Effect of vibration on pain during subcutaneous heparin injection: A randomized, single-blind, placebo-controlled trial
  150. The diagnostic performance of machine learning-based FFRCT for coronary artery disease: A meta-analysis
  151. Comparing biofeedback device vs diaphragmatic breathing for bloating relief: A randomized controlled trial
  152. Serum uric acid to albumin ratio and C-reactive protein as predictive biomarkers for chronic total occlusion and coronary collateral circulation quality
  153. Multiple organ scoring systems for predicting in-hospital mortality of sepsis patients in the intensive care unit
  154. Single-cell RNA sequencing data analysis of the inner ear in gentamicin-treated mice via intraperitoneal injection
  155. Review Articles
  156. The effects of enhanced external counter-pulsation on post-acute sequelae of COVID-19: A narrative review
  157. Diabetes-related cognitive impairment: Mechanisms, symptoms, and treatments
  158. Microscopic changes and gross morphology of placenta in women affected by gestational diabetes mellitus in dietary treatment: A systematic review
  159. Review of mechanisms and frontier applications in IL-17A-induced hypertension
  160. Research progress on the correlation between islet amyloid peptides and type 2 diabetes mellitus
  161. The safety and efficacy of BCG combined with mitomycin C compared with BCG monotherapy in patients with non-muscle-invasive bladder cancer: A systematic review and meta-analysis
  162. The application of augmented reality in robotic general surgery: A mini-review
  163. The effect of Greek mountain tea extract and wheat germ extract on peripheral blood flow and eicosanoid metabolism in mammals
  164. Neurogasobiology of migraine: Carbon monoxide, hydrogen sulfide, and nitric oxide as emerging pathophysiological trinacrium relevant to nociception regulation
  165. Plant polyphenols, terpenes, and terpenoids in oral health
  166. Laboratory medicine between technological innovation, rights safeguarding, and patient safety: A bioethical perspective
  167. End-of-life in cancer patients: Medicolegal implications and ethical challenges in Europe
  168. The maternal factors during pregnancy for intrauterine growth retardation: An umbrella review
  169. Intra-abdominal hypertension/abdominal compartment syndrome of pediatric patients in critical care settings
  170. PI3K/Akt pathway and neuroinflammation in sepsis-associated encephalopathy
  171. Screening of Group B Streptococcus in pregnancy: A systematic review for the laboratory detection
  172. Giant borderline ovarian tumours – review of the literature
  173. Leveraging artificial intelligence for collaborative care planning: Innovations and impacts in shared decision-making – A systematic review
  174. Cholera epidemiology analysis through the experience of the 1973 Naples epidemic
  175. Risk factors of frailty/sarcopenia in community older adults: Meta-analysis
  176. Supplement strategies for infertility in overweight women: Evidence and legal insights
  177. Scurvy, a not obsolete disorder: Clinical report in eight young children and literature review
  178. A meta-analysis of the effects of DBS on cognitive function in patients with advanced PD
  179. Protective role of selenium in sepsis: Mechanisms and potential therapeutic strategies
  180. Strategies for hyperkalemia management in dialysis patients: A systematic review
  181. C-reactive protein-to-albumin ratio in peripheral artery disease
  182. Case Reports
  183. Delayed graft function after renal transplantation
  184. Semaglutide treatment for type 2 diabetes in a patient with chronic myeloid leukemia: A case report and review of the literature
  185. Diverse electrophysiological demyelinating features in a late-onset glycogen storage disease type IIIa case
  186. Giant right atrial hemangioma presenting with ascites: A case report
  187. Laser excision of a large granular cell tumor of the vocal cord with subglottic extension: A case report
  188. EsoFLIP-assisted dilation for dysphagia in systemic sclerosis: Highlighting the role of multimodal esophageal evaluation
  189. Molecular hydrogen-rhodiola as an adjuvant therapy for ischemic stroke in internal carotid artery occlusion: A case report
  190. Coronary artery anomalies: A case of the “malignant” left coronary artery and its surgical management
  191. Rapid Communication
  192. Biological properties of valve materials using RGD and EC
  193. A single oral administration of flavanols enhances short-term memory in mice along with increased brain-derived neurotrophic factor
  194. Letter to the Editor
  195. Role of enhanced external counterpulsation in long COVID
  196. Expression of Concern
  197. Expression of concern “A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma”
  198. Expression of concern “Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway”
  199. Expression of concern “circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8”
  200. Corrigendum
  201. Corrigendum to “Empagliflozin improves aortic injury in obese mice by regulating fatty acid metabolism”
  202. Corrigendum to “Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis”
  203. Corrigendum to “The progress of autoimmune hepatitis research and future challenges”
  204. Retraction
  205. Retraction of “miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway”
  206. Retraction of: “LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through downregulating SP-A by sponging to miR-424”
  207. Retraction of: “SCARA5 inhibits oral squamous cell carcinoma via inactivating the STAT3 and PI3K/AKT signaling pathways”
  208. Special Issue Advancements in oncology: bridging clinical and experimental research - Part II
  209. Unveiling novel biomarkers for platinum chemoresistance in ovarian cancer
  210. Lathyrol affects the expression of AR and PSA and inhibits the malignant behavior of RCC cells
  211. The era of increasing cancer survivorship: Trends in fertility preservation, medico-legal implications, and ethical challenges
  212. Bone scintigraphy and positron emission tomography in the early diagnosis of MRONJ
  213. Meta-analysis of clinical efficacy and safety of immunotherapy combined with chemotherapy in non-small cell lung cancer
  214. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part IV
  215. Exploration of mRNA-modifying METTL3 oncogene as momentous prognostic biomarker responsible for colorectal cancer development
  216. Special Issue The evolving saga of RNAs from bench to bedside - Part III
  217. Interaction and verification of ferroptosis-related RNAs Rela and Stat3 in promoting sepsis-associated acute kidney injury
  218. The mRNA MOXD1: Link to oxidative stress and prognostic significance in gastric cancer
  219. Special Issue Exploring the biological mechanism of human diseases based on MultiOmics Technology - Part II
  220. Dynamic changes in lactate-related genes in microglia and their role in immune cell interactions after ischemic stroke
  221. A prognostic model correlated with fatty acid metabolism in Ewing’s sarcoma based on bioinformatics analysis
  222. Red cell distribution width predicts early kidney injury: A NHANES cross-sectional study
  223. Special Issue Diabetes mellitus: pathophysiology, complications & treatment
  224. Nutritional risk assessment and nutritional support in children with congenital diabetes during surgery
  225. Correlation of the differential expressions of RANK, RANKL, and OPG with obesity in the elderly population in Xinjiang
  226. A discussion on the application of fluorescence micro-optical sectioning tomography in the research of cognitive dysfunction in diabetes
  227. A review of brain research on T2DM-related cognitive dysfunction
  228. Metformin and estrogen modulation in LABC with T2DM: A 36-month randomized trial
  229. Special Issue Innovative Biomarker Discovery and Precision Medicine in Cancer Diagnostics
  230. CircASH1L-mediated tumor progression in triple-negative breast cancer: PI3K/AKT pathway mechanisms
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 25.11.2025 from https://www.degruyterbrill.com/document/doi/10.1515/med-2025-1237/html
Scroll to top button