BACKGROUND & AIMS:Primary sclerosing cholangitis (PSC) has a variable disease course, complicating patient counseling and the timing of liver transplantation. Vitamin B6 deficiency predicts reduced liver transplantation-free survival in Scandinavian PSC cohorts. Here, we aimed to validate this observation in US and German PSC cohorts and to expand our analyses to include hepatic decompensation as a clinical outcome. METHODS:Serum active vitamin B6 (pyridoxal 5'-phosphate [PLP]) was analyzed using liquid chromatography-tandem mass spectrometry in retrospective cohorts of people with PSC from Norway (n = 315), the USA (n = 756), and Germany (n = 149). Cox proportional hazards and Fine and Gray competing risk models were fitted to estimate the ability of PLP to predict liver transplantation-free survival and the cumulative incidence of hepatic decompensation, respectively. RESULTS:The prevalence of vitamin B6 deficiency (PLP <20 nmol/L) in pre-transplant PSC was 50% in the Norway cohort and 25% in the USA cohort. The prevalence was higher among those with previous hepatic decompensation. The cumulative incidence of hepatic decompensation was higher in the USA cohort, while individuals in the Norway cohort were more commonly transplanted for indications other than hepatic decompensation. Despite differences in clinical practice, low PLP was consistently associated with shorter liver transplantation-free survival, and PLP added predictive value for liver transplantation or death from PSC over and above contemporary prediction models. Low PLP was also associated with a higher incidence of hepatic decompensation, which was mainly evident in the USA cohort, where decompensation was more common. The risk of both outcomes increased sharply within the deficient and marginal ranges and plateaued at sufficient PLP levels. CONCLUSIONS:Vitamin B6 deficiency is common in PSC outside Scandinavia and is consistently associated with poor outcomes across geographically distinct PSC populations. IMPACT AND IMPLICATIONS:We previously showed that vitamin B6 deficiency is prevalent and associated with reduced liver transplantation-free survival in Scandinavian PSC cohorts. The current work shows that these observations generalize to a US population and that low vitamin B6 is also associated with the development of hepatic decompensation. Our results indicate that vitamin B6 provides incremental value for predicting outcomes in PSC across geographically distinct populations and that efforts to restore B6 sufficiency should be focused on the many individuals who present with vitamin B6 levels within the marginal-to-definitive deficiency range.

Background:We explored factors associated with left ventricular (LV) mass index during biological (b) or targeted synthetic (ts) disease modifying antirheumatic drug (DMARD) therapy in patients with rheumatoid arthritis (RA). Methods:Eighty-three outpatients with RA (age 55 ± 12 years, 71% women) with an indication for b/ts DMARD therapy were examined with echocardiography at baseline and after a mean follow-up of 22 months. LV mass was calculated according to guidelines and indexed for height2.7. Results:At baseline, 37% had hypertension, 6% diabetes, 21% obesity, and 100% were using b/ts DMARDs. During follow-up, 17% discontinued b/tsDMARD treatment. The LV mass index remained unchanged during follow-up (33.1 ± 8.1 g/m2.7 vs. 33.5 ± 7.3 g/m2.7, p = 0.57, mean change 0.3 ± 4.9 g/m2.7). Lower LV mass index at follow-up was observed in patients using bDMARDs at follow-up (31.7 ± 6.2 g/m2.7 vs. 36.6 ± 8.9 g/m2.7, p = 0.001). In multivariable linear regression analyses, use of bDMARDs (β -0.22, p = 0.03) at follow-up were associated with lower LV mass index at follow-up, independent of C-reactive protein (CRP), age, sex, and obesity at baseline. Obesity at baseline (β 0.39, p < 0.001) was associated with a higher LV mass index both at baseline and follow-up. Higher CRP at baseline was associated with higher LV mass index at baseline (β 0.31, p = 0.001), but not at follow-up. Conclusion:In patients with RA on DMARD treatment, the mean LV mass index remained stable during 22 months of follow-up. Obesity was the strongest factor associated with higher LV mass index, while use of bDMARD throughout the study period was associated with lower LV mass index.

Disclosure: M.T. Neset: None. A. Ulvik: None. K. Løvås: None. J. Laupsa-Borge: None. L.E. Breivik: None. A.M. Stokland: None. B. Nedrebø: None. E. Rødahl: None. E.S. Husebye: None. G.Å. Ueland: None. H. Ueland: None. Objective: Graves` disease increases metabolism and leads to net lipid degradation. Circulating acylcarnitines reflect lipid metabolism and state of fatty acid oxidation in the individuals. The aim of this study was to explore the lipid and acylcarnitine profiles in patients with Graves` disease. Methods: Seven lipids/apolipoproteins and 23 acylcarnitines were analyzed in 100 newly diagnosed Graves` disease patients and validated in another 51 patients. Both groups were age- and sex- matched with healthy subjects. Results: Graves` disease patients from the main cohort (87 females, median age 42.5 (17-67) years), had significantly (p < 0.05) higher levels of medium- and long-chain acylcarnitines, and lower levels of short-chain acylcarnitines, compared with healthy subjects. Factor analysis showed that medium- and long-chain acylcarnitines explained most of the differences between the two groups. Serum levels of the seven lipids/apolipoproteins were significantly lower in Graves` disease patients compared to healthy subjects. Patients (n=21) treated with antithyroid drugs for six weeks had acylcarnitines levels closer to healthy subjects, when compared to 79 treatment-naïve hyperthyroid patients. The main findings were confirmed in the validation group. Conclusion: Increased levels of medium- and long-chain acylcarnitines in patients with newly diagnosed Graves` disease may reflect increased heart activity and accelerated catabolism in skeletal muscles. Lower levels of short-chain acylcarnitines point to Graves` disease being a catabolic condition with a shift in energy source from carbohydrates to fat. Presentation: Monday, July 14, 2025

Our objective was to explore whether plasma inflammatory biomarkers and related metabolites in acute phase and 3 months after stroke were associated with different cognitive trajectories and with changes in cognition post-stroke. The Norwegian Cognitive Impairment After Stroke (Nor-COAST) study was a prospective, multicentre cohort study of patients with acute stroke, followed up at 3, 18, and 36 months post-stroke. First, we modelled cognitive trajectory groups based on Montreal Cognitive Assessment (MoCA) scores and used multinominal logistic regression to study the associations between systemic inflammatory biomarkers/metabolites and group membership. Second, using mixed linear regression, we investigated whether the same biomarkers/metabolites were associated with changes in MoCA scores over time, stratified by pre-stroke cognitive status. The 466 participants had mean (SD) age 72 (12) years, 59% were males, and mean (SD) NIHSS score at admittance was 4 (4.8). Higher acute-phase values of the terminal complement complex, interleukin 6, macrophage inflammatory protein 1α, neopterin, quinolinic acid, and PA ratio = 4-pyridoxic acid / (pyridoxal + pyridoxal 5’-phosphate) and higher 3-month values of neopterin were associated with increased risk of being in the group characterized by low and declining MoCA score compared to the group of best MoCA score ( p < 0.01). Higher acute-phase values of tumour necrosis factor and interleukin 8, were associated with progressive decline in the MoCA score ( p < 0.01). Premorbid factors, and in particular pre-stroke frailty, had more impact on the models than stroke-related factors, and partly confounded several of these associations. Higher degrees of systemic inflammation in the acute phase were associated with worse cognitive trajectories and may reflect the response to the acute stroke, stroke-related complications and/or premorbid conditions. Trial registration: ClinicalTrials.gov: NCT02650531. Retrospectively registered January 8, 2016. First participant included May 18, 2015.

BACKGROUND:Low concentrations of biologically active B6 vitamer, pyridoxal 5'-phosphate (PLP) are associated with an increased risk of cardiovascular disease (CVD). Vitamin A (Vit-A) promotes lipid homeostasis and the transport cholesterol. Vit-A may also stimulate the intracellular transport of PLP. OBJECTIVES:This study aimed to investigate whether Vit-A is associated with variations in the relationship of systemic B6-vitamers with incident acute myocardial infarctions (AMIs). METHODS:A total of 4091 patients undergoing elective coronary angiography for suspected stable angina pectoris were studied. Associations of different plasma B6 vitamers, including PLP, pyridoxal (PL), 4-pyridoxic acid (PA), and PA/PL ratio with the risk of AMI according to median concentrations of Vit-A, were explored in Cox regression models. RESULTS:Serum Vit-A demonstrated positive associations with PLP and PA/PL ratio at baseline (P < 0.001 for both). During a median follow-up of 7.5 y, 521 (12.7%) patients suffered an AMI. In age and sex-adjusted analyses, plasma PLP, PA, and PA/PL ratio showed an overall association with incident AMI {hazard ratio (HR) [95% confidence interval (CI)] per SD: 0.90 [0.82, 0.99; P = 0.02], 1.14 [1.05, 1.23; P < 0.001], and 1.28 [1.18, 1.39; P < 0.001], respectively}. However, low plasma PLP and high PA/PL ratio were associated with an increased risk of AMI primarily among patients with high compared with low Vit-A concentrations [HR (95% CI) per SD: 0.77 (0.68, 0.88; P < 0.001, P-interaction = 0.002) and 1.36 (1.23, 1.49; P < 0.001, P-interaction = 0.05), respectively]. The interactions persisted after multivariable adjustment (both P-interactions ≤ 0.04). CONCLUSIONS:The relationship between vitamin B6 indexes and AMI risk varied according to serum Vit-A concentrations. Additional research is needed to clarify the importance of Vit-A and B6 bioavailability in atherosclerotic CVD. This trial was registered at clinicaltrials.gov as NCT00354081.

ObjectivesIndications of mitochondrial dysfunction are commonly seen in liver diseases, but data are scarce in primary sclerosing cholangitis (PSC). Analyzing circulating and liver-resident molecules indirectly reflecting mitochondrial dysfunction, we aimed to comprehensively characterize this deficit in PSC, and whether this was PSC specific or associated with cholestasis.Materials and methodsWe retrospectively included plasma from 191 non-transplant patients with large-duct PSC and 100 healthy controls and explanted liver tissue extracts from 24 PSC patients and 18 non-cholestatic liver disease controls. Using mass spectroscopy, we profiled lipids and fatty acids, carnitine, acylcarnitines, and metabolites in the tryptophan-kynurenine-nicotinamide pathway.ResultsHierarchal clustering of fatty acid levels identified patients with PSC and healthy controls as separate clusters. Compared to healthy controls, PSC patients had increased levels of monounsaturated fatty acids (MUFA) and palmitate (C16:0) in plasma, but reduced levels of long-chain saturated fatty acids (SFAs). These findings were more pronounced in PSC patients with cholestasis. Several n-3 polyunsaturated fatty acids were elevated in PSC but not associated with cholestasis. Acylcarnitine ratios C2/C5 and C2/C3 were elevated while C2/C16 was reduced in PSC, indicating impaired mitochondrial fatty acid oxidation of medium-long chained fatty acids. Levels of intermediates in the tryptophan-kynurenine pathway indicated impaired NAD biosynthesis, suggesting impaired energy supply to mitochondria in PSC.ConclusionsWe found that mitochondrial dysfunction was prominent in PSC and associated with increasing cholestasis. Whether this is merely a marker of liver disease and severity, or an underlying driver and potential therapeutic target in PSC remains to be explored.

Recent studies demonstrate that Parkinson’s disease (PD) is associated with dysregulated metabolic flux through the kynurenine pathway (KP), in which tryptophan is converted to kynurenine (KYN), and KYN is subsequently metabolized to neuroactive compounds quinolinic acid (QA) and kynurenic acid (KA). Here, we used mass-spectrometry to compare blood and cerebral spinal fluid (CSF) KP metabolites between 158 unimpaired older adults and 177 participants with PD. We found increased neuroexcitatory QA/KA ratio in both plasma and CSF of PD participants associated with peripheral and cerebral inflammation and vitamin B6 deficiency. Furthermore, increased QA tracked with CSF tau, CSF soluble TREM2 (sTREM2) and severity of both motor and non-motor PD clinical symptoms. Finally, PD patient subgroups with distinct KP profiles displayed distinct PD clinical features. These data validate the KP as a site of brain and periphery crosstalk, integrating B-vitamin status, inflammation and metabolism to ultimately influence PD clinical manifestation.

The tryptophan-kynurenine pathway may play a role in cognitive decline in both neurodegenerative and cerebrovascular disorders. However, clinical studies investigating kynurenines so far have generally been small, and studies looking into prodromal disease stages are scarce. The present study used a transdiagnostic approach to investigate levels of kynurenines and B-vitamins, as important cofactors, across diagnostic phases of dementia and healthy controls. Blood plasma levels of tryptophan, seven kynurenine metabolites (kynurenine, 3-hydroxykynurenine, kynurenic acid, xanthurenic acid, anthranilic acid, 3-hydroxyanthranilic acid, quinolinic acid) and B-vitamins (pyridoxal 5’-phosphate and riboflavin) were determined in 2,452 cognitively healthy older adults (used as controls) from the population-based The Maastricht Study, 759 patients from a memory clinic, including patients with subjective cognitive decline (SCD, n = 293), mild cognitive impairment (MCI, n = 304) or dementia ( n  = 162, and in 194 patients 3 months after stroke with (PSCI, n = 127) or without post-stroke cognitive impairment (PSNCI, n = 67). Samples were analyzed by Bevital, Bergen, Norway, by means of LC-MS/MS. Linear regression analyses were done to assess differences between cohorts and across diagnostic phases, while adjusting for a priori defined confounders (demographics, kidney function, and lifestyle factors). Where appropriate, metabolites were log-transformed prior to analysis and all were standardized for reasons of comparison. Preliminary results showed that, in analyses comparing stroke patients to controls, plasma levels of tryptophan (-0.36 [-0.52, -0.21]), xanthurenic acid (-0.15 [-0.26, -0.00]), kynurenic acid-to-quinolinic acid ratio (-0.45 [-0.60, -0.29]), pyridoxal 5’-phosphate (-0.69 [-0.84, -0.54]), and riboflavin (-0.43 [-0.58, -0.27]) were significantly lower, while levels of kynurenine (0.28 [0.15, 0.41]), 3-hydroxykynurenine (0.70 [0.56, 0.84]), 3-hydroxyanthranilic acid (0.45 [0.30, 0.59]), quinolinic acid (0.46 [0.33, 0.60]), and kynurenine-to-tryptophan ratio (0.53 [0.40, 0.66]) were higher. No difference were found in kynurenic acid (0.00 [-0.23, 0.13]) or anthranilic acid (0.01 [-0.14, 0.16]). Results were similar for patients with PSCI and PSNCI, with no significant differences between these groups. Analyses in the memory clinic population are currently being performed. These preliminary results suggest that the kynurenine pathway is dysregulated after stroke, independent of cognitive impairment. Further studies are needed to validate these findings.

Objective: Graves' disease increases metabolism and leads to net lipid degradation. Circulating acylcarnitines reflect lipid metabolism and the state of fatty acid oxidation in individuals. The aim of this study was to explore the lipid and acylcarnitine profiles in patients with Graves' disease. Methods: Seven lipids/apolipoproteins and 23 acylcarnitines were analysed in 100 newly diagnosed Graves' disease patients and validated in another 51 patients. Both groups were age- and sex-matched with healthy subjects. Results: The hyperthyroid Graves' disease patients (n = 88) from the main cohort (78 females, median age 42 (17–67) years) had significantly (P < 0.05) higher levels of medium- and long-chain acylcarnitines, and lower levels of short-chain acylcarnitines, compared with healthy subjects. Factor analysis showed that medium- and long-chain acylcarnitines explained most of the differences between the two groups. Serum levels of the five lipids/apolipoproteins were significantly lower in the hyperthyroid Graves' disease patients compared with healthy subjects. Patients (n = 21) treated with antithyroid drugs for 6 weeks had acylcarnitine levels closer to healthy subjects, compared with 79 treatment-naïve hyperthyroid patients. The main findings were confirmed in the validation group. Conclusion: Increased levels of medium- and long-chain acylcarnitines in patients with newly diagnosed Graves' disease may reflect accelerated catabolism. Lower levels of short-chain acylcarnitines point to Graves' disease being a catabolic condition, with a shift in energy source from carbohydrates to fat.

OBJECTIVES:The aim was to investigate whether kynurenine pathway metabolites and neopterin increase probability for Sjögren's disease (SjD) and their associations with clinical parameters and inflammatory biomarkers. METHODS:In this case-control study, 97 SjD patients and 63 age- and sex-matched healthy volunteers were enrolled. Clinical and immunological characteristics, EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) and the EULAR Sjögren's Syndrome Patient-Report Index (ESSPRI) were evaluated. High-sensitivity C-reactive protein (hs-CRP), cysteine, leptin, resistin, adiponectin, interleukins, chemokines and TNF receptors I and II were analyzed using a multiplex system. The concentrations of cystatin-C, neopterin, tryptophan, vitamin B6 and kynurenine metabolites were assessed using liquid chromatography-tandem mass spectrometry. RESULTS:Tryptophan levels were lower in SjD (P = 0.012), and kynurinine (P = 0.005), kynurenine/tryptophan ratio (KTR) (P = 0.001) and neopterin (P = 0.02) were higher. Kynurenine (OR 2.51, 95%CI 1.44-5.64), KTR (OR 3.45, 95% CI 1.76-6.74), neopterin (OR 4.28, 95% CI 1.95-9.42) and vitamin B6 metabolite (PAr) (OR 3.34, 95% CI 1.19-9.39) increased the chances for SjD. They were associated with disease activity, longer disease duration, depression, impaired salivary flow, hypergammaglobulinemia, neutropenia, hypocomplementemia and positive anti-Ro/SSA and anti-La/SSB. Neopterin correlated with kynurenines, and both were also associated with PAr and pro-inflammatory cytokines, mainly TNF-α, IL-1β and TNF receptors I and II. CONCLUSION:Kynurenines and neopterin are interferon-gamma-inducible biomarkers associated with more chances for SjD and with disease activity, glandular dysfunction, autoantibodies and immunological and inflammatory biomarkers.

BACKGROUND:The tryptophan-kynurenine pathway may play a role in cognitive decline in both neurodegenerative and cerebrovascular disorders. However, clinical studies investigating kynurenines so far have generally been small, and studies looking into prodromal disease stages are scarce. The present study used a transdiagnostic approach to investigate levels of kynurenines and B-vitamins, as important cofactors, across diagnostic phases of dementia and healthy controls. METHOD:Blood plasma levels of tryptophan, seven kynurenine metabolites (kynurenine, 3-hydroxykynurenine, kynurenic acid, xanthurenic acid, anthranilic acid, 3-hydroxyanthranilic acid, quinolinic acid) and B-vitamins (pyridoxal 5'-phosphate and riboflavin) were determined in 2,452 cognitively healthy older adults (used as controls) from the population-based The Maastricht Study, 759 patients from a memory clinic, including patients with subjective cognitive decline (SCD, n = 293), mild cognitive impairment (MCI, n = 304) or dementia (n = 162, and in 194 patients 3 months after stroke with (PSCI, n = 127) or without post-stroke cognitive impairment (PSNCI, n = 67). Samples were analyzed by Bevital, Bergen, Norway, by means of LC-MS/MS. Linear regression analyses were done to assess differences between cohorts and across diagnostic phases, while adjusting for a priori defined confounders (demographics, kidney function, and lifestyle factors). Where appropriate, metabolites were log-transformed prior to analysis and all were standardized for reasons of comparison. RESULT:Preliminary results showed that, in analyses comparing stroke patients to controls, plasma levels of tryptophan (-0.36 [-0.52, -0.21]), xanthurenic acid (-0.15 [-0.26, -0.00]), kynurenic acid-to-quinolinic acid ratio (-0.45 [-0.60, -0.29]), pyridoxal 5'-phosphate (-0.69 [-0.84, -0.54]), and riboflavin (-0.43 [-0.58, -0.27]) were significantly lower, while levels of kynurenine (0.28 [0.15, 0.41]), 3-hydroxykynurenine (0.70 [0.56, 0.84]), 3-hydroxyanthranilic acid (0.45 [0.30, 0.59]), quinolinic acid (0.46 [0.33, 0.60]), and kynurenine-to-tryptophan ratio (0.53 [0.40, 0.66]) were higher. No difference were found in kynurenic acid (0.00 [-0.23, 0.13]) or anthranilic acid (0.01 [-0.14, 0.16]). Results were similar for patients with PSCI and PSNCI, with no significant differences between these groups. Analyses in the memory clinic population are currently being performed. CONCLUSION:These preliminary results suggest that the kynurenine pathway is dysregulated after stroke, independent of cognitive impairment. Further studies are needed to validate these findings.

BACKGROUND:The kynurenine pathway, the main metabolic pathway of tryptophan degradation, has been mostly studied in neurodegenerative disorders, while its role in cerebrovascular pathology is less clear. We investigated whether kynurenines are associated with markers of neurodegeneration and cerebrovascular pathology in the general population. METHODS:Cross-sectional data was used from 1589 individuals (60.0 ± 8.0 years, 54.3 % men) who participated in The Maastricht Study, an observational population-based cohort study. Plasma concentrations of tryptophan, kynurenines, and neopterin were quantified. Neurodegeneration was measured by volumes of intracranial cerebrospinal fluid (CSF), while cerebrovascular pathology was measured by white matter hyperintensity (WMH) volume and presence of cerebral small vessel disease (cSVD), defined as the presence of lacunar infarcts, cerebral microbleeds or a Fazekas score ≥ 2, all derived from 3 T MRI. Associations of kynurenines with these markers were investigated using linear, logistic, and restricted cubic spline regression models adjusted for confounders. RESULTS:Fully adjusted analyses indicated that higher levels of 3-hydroxyanthranilic acid, kynurenine, kynurenic acid, quinolinic acid, and neopterin were associated with lower CSF volume. For the latter four, associations were non-linear and restricted to participants with already below average concentrations. Higher levels of tryptophan and anthranilic acid were associated with higher CSF volumes in participants with above-average levels. Higher levels of the kynurenine-tryptophan ratio were associated with a lower WMH volume. No evidence was found for associations between individual kynurenines and WMH volume or cSVD presence. CONCLUSIONS:These findings suggest that several kynurenines are associated with neurodegeneration in community-dwelling older adults, but not with cerebrovascular damage.

BACKGROUND:Emerging evidence suggests that nutritional prehabilitation reduces risk of complications after colorectal cancer (CRC) surgery. The gut microbiota and its metabolic activity potentially link preoperative diet to postoperative outcomes. OBJECTIVE:To investigate associations between preoperative plasma levels of microbial-derived metabolites and postoperative complications in patients with CRC. METHODS:We used data from a prospective cohort study among 1220 patients with nonmetastatic CRC. The short-chain fatty acids (SCFAs) acetate, propionate, butyrate, and valerate, as well as the branched-chain fatty acids (BCFAs) isovalerate, isobutyrate, and α-methylbutyrate, were measured in plasma collected at diagnosis. Prevalence ratios (PR) were calculated using regression models adjusted for age, sex, tumor location, smoking status, and physical health status. RESULTS:Acetate levels of 40.0 μmol/L were associated with a lower risk of any postoperative complications compared with the reference of 20.0 μmol/L [PR: 0.76; 95% confidence interval (CI): 0.62, 0.93]. Higher levels of propionate (per 1 μmol/L) were associated with a lower risk of any complications (PR: 0.84; 95% CI: 0.73, 0.96). Similar associations were found for acetate (per 20 μmol/L) and propionate (per 1 μmol/L) in relation to surgical complications (PR: 0.75; 95% CI: 0.60, 0.93; and PR: 0.83; 95% CI: 0.69, 1.00; respectively). No associations were found for BCFAs in relation to complications. Low (below median) total SCFA levels combined with high (above median) total BCFA levels were least favorable in terms of complication risk (PR: 1.35; 95% CI: 1.02, 1.80) when compared with a low SCFA/low BCFA profile. CONCLUSIONS:Our findings suggest that microbial fermentation processes, mainly those resulting in higher SCFA levels, may be linked to postoperative recovery. These findings provide leads for future studies investigating the role of preoperative diet, especially the balance between fiber and protein intake, and microbial metabolism in relation to postoperative recovery of patients with CRC. This study was registered at clinicaltrials.gov with registration number NCT03191110.

Alterations within the tryptophan-kynurenine metabolic pathway have been linked to the etiology of colorectal cancer (CRC), but the relevance of this pathway for prognostic outcomes in CRC patients needs further elucidation. Therefore, we investigated associations between circulating concentrations of tryptophan-kynurenine pathway metabolites and all-cause mortality among CRC patients. This study utilizes data from 2102 stage I-III CRC patients participating in six prospective cohorts involved in the international FOCUS Consortium. Preoperative circulating concentrations of tryptophan, kynurenine, kynurenic acid (KA), 3-hydroxykynurenine (HK), xanthurenic acid (XA), 3-hydroxyanthranilic acid (HAA), anthranilic acid (AA), picolinic acid (PA), and quinolinic acid (QA) were measured by liquid chromatography-tandem mass spectrometry. Using Cox proportional hazards regression, we examined associations of above-mentioned metabolites with all-cause mortality, adjusted for potential confounders. During a median follow-up of 3.2 years (interquartile range: 2.2-4.9), 290 patients (13.8%) deceased. Higher blood concentrations of tryptophan, XA, and PA were associated with a lower risk of all-cause mortality (per doubling in concentrations: tryptophan: HR = 0.56; 95%CI:0.41,0.76, XA: HR = 0.74; 95%CI:0.64,0.85, PA: HR = 0.76; 95%CI:0.64,0.92), while higher concentrations of HK and QA were associated with an increased risk of death (per doubling in concentrations: HK: HR = 1.80; 95%CI:1.47,2.21, QA: HR = 1.31; 95%CI:1.05,1.63). A higher kynurenine-to-tryptophan ratio, a marker of cell-mediated immune activation, was associated with an increased risk of death (per doubling: HR = 2.07; 95%CI:1.52,2.83). In conclusion, tryptophan-kynurenine pathway metabolites may be prognostic markers of survival in CRC patients.

ObjectiveChronic chemotherapy-induced peripheral neuropathy (CIPN) is a long-lasting side-effect of oxaliplatin. Vitamin B6 might play a role in the pathogenesis of CIPN. Therefore, we investigated associations between plasma vitamin B6 markers and the occurrence and severity of chronic CIPN in patients with non-metastatic colorectal cancer (CRC).Methods and analysis242 patients with CRC receiving oxaliplatin-based chemotherapy were included. Blood samples were collected at diagnosis (ie, before chemotherapy), and 6 and 12 months after diagnosis (ie, during and after chemotherapy, respectively). Pyridoxal 5′-phosphate (PLP), pyridoxal (PL) and xanthurenic acid:3-hydroxykynurenine (XA:HK) ratio were measured as vitamin B6 markers using liquid chromatography tandem mass spectrometry. Chronic CIPN was assessed 12 months after diagnosis using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-CIPN twenty-item scale questionnaire. Prevalence ratios (PRs) and restricted cubic splines (RCSs) were used to assess associations with chronic CIPN occurrence, and linear regressions were used to assess associations with chronic CIPN severity. Analyses were adjusted for age, sex, smoking, alcohol consumption, diabetes and timing of chemotherapy (neoadjuvant/adjuvant/both).ResultsChronic CIPN was found in 80% (n=194) of patients. Higher PLP levels and XA:HK ratios during chemotherapy were associated with lower occurrence of chronic CIPN (PRperdoubling0.75, 95% CI 0.62 to 0.91 and PRCS<0.05, respectively) and lower chronic CIPN severity (βperdoubling−4.54, 95% CI −7.12 to −1.96 and βperdoubling−6.30, 95% CI −9.53 to −3.07, respectively). No associations between PL levels and chronic CIPN were observed.ConclusionWithin this population, merely having PLP levels within the normal range, higher vitamin B6 status during chemotherapy was associated with lower occurrence and severity of chronic CIPN. Future research is warranted to investigate causality and the optimal vitamin B6 status during chemotherapy.

Abstract Background Sex differences in neuroinflammation could contribute to women’s increased risk of Alzheimer’s disease (AD), providing rationale for exploring sex-specific AD biomarkers. In AD, dysregulation of the kynurenine pathway (KP) contributes to neuroinflammation and there is some evidence of sex differences in KP metabolism. However, the sex-specific associations between KP metabolism and biomarkers of AD and neuroinflammation need to be explored further. Methods Here we investigate sex differences in cerebrospinal fluid concentrations of seven KP metabolites and sex-specific associations with established AD biomarkers and neopterin, an indicator of neuroinflammation. This study included 311 patients with symptomatic AD and 105 age-matched cognitively unimpaired (CU) controls, followed for up to 5 years. Results We found sex differences in KP metabolites in the AD group, with higher levels of most metabolites in men, while there were no sex differences in the CU group. In line with this, more KP metabolites were significantly altered in AD men compared to CU men, and there was a trend in the same direction in AD women. Furthermore, we found sex-specific associations between kynurenic acid and the kynurenic acid/quinolinic acid ratio with neopterin, but no sex differences in the associations between KP metabolites and clinical progression. Discussion In our cohort, sex differences in KP metabolites were restricted to AD patients. Our results suggest that dysregulation of the KP due to increased inflammation could contribute to higher AD risk in women.

Background and aims: We have previously shown that systemic inflammation was associated with post-stroke cognitive impairment (PSCI). Because neopterin, kynurenine pathway (KP) metabolites, and B6 vitamers are linked to inflammation, in our study we investigated whether those biomarkers were associated with PSCI. Material and methods: The Norwegian Cognitive Impairment After Stroke study is a prospective multicenter cohort study of patients with acute stroke recruited from May 2015 through March 2017. Plasma samples of 422 participants (59 % male) with ischemic stroke from the index hospital stay and 3 months post-stroke were available for analyses of neopterin, KP metabolites, and B6 vitamers using liquid chromatography-tandem mass spectrometry. Mixed linear regression analyses adjusted for age, sex, and creatinine, were used to assess whether there were associations between those biomarkers and cognitive outcomes, measured by the Montreal Cognitive Assessment scale (MoCA) at 3-, 18-, and 36-month follow-up. Results: Participants had a mean (SD) age of 72 (12) years, with a mean (SD) National Institutes of Health Stroke Scale score of 2.7 (3.6) at Day 1. Higher baseline values of quinolinic acid, PAr (i.e., an inflammatory marker based on vitamin B6 metabolites), and HKr (i.e., a marker of functional vitamin B6 status based on selected KP metabolites) were associated with lower MoCA score at 3, 18, and 36 months post-stroke (p < 0.01). Higher baseline concentrations of neopterin and 3-hydroxykynurenine were associated with lower MoCA scores at 18 and 36 months, and higher concentrations of xanthurenic acid were associated with higher MoCA score at 36 months (p < 0.01). At 3 months post-stroke, higher concentrations of neopterin and lower values of pyridoxal 5-phosphate were associated with lower MoCA scores at 18- and 36-month follow-up, while lower concentrations of picolinic acid were associated with a lower MoCA score at 36 months (p < 0.01). Conclusion: Biomarkers and metabolites of systemic inflammation, including biomarkers of cellular immune activation, indexes of vitamin B6 homeostasis, and several neuroactive metabolites of the KP pathway, were associated with PSCI. Trial registration: ClinicalTrials.gov: NCT02650531.

Abstract Introduction: Dysregulation of the kynurenine pathway of tryptophan metabolism has been linked to the development of inflammation-related chronic diseases, such as colorectal cancer (CRC). Circulating concentrations of certain kynurenine metabolites, the kynurenine/tryptophan ratio (KTR), and the pro-inflammatory marker neopterin increase during inflammation, particularly in response to interferon-gamma. However, comprehensive data on the associations between inflammation markers and kynurenine metabolites and clinical outcomes in CRC patients are lacking. To address this gap in knowledge, we investigated associations of circulating kynurenine metabolites and neopterin with overall survival (OS) in prospectively followed non-metastatic CRC patients. Methods: Pre-surgery blood samples from 2,101 stage I-III CRC patients participating in the international FOCUS consortium were used to measure circulating levels of nine tryptophan-kynurenine pathway metabolites and neopterin using liquid chromatography-tandem mass spectrometry. Multivariable linear regression models and Spearman partial correlation analyses were conducted to quantify associations between kynurenine metabolites and neopterin. Based on the results from correlation analyses, a subset of patients (n=984) was categorized into different groups (‘kynurenine metabolite/neopterin‘: i.e. ‘low/high‘, ‘high/high‘) using the median biomarker concentration as cut-off. Associations of biomarkers with OS were assessed using Cox proportional hazards regression models. All models were adjusted for age at diagnosis, sex, tumor stage, tumor site, circulating creatine levels and cohort. Results: Tryptophan was inversely correlated with neopterin (r=−0.21, β=−0.48, Plinear<0.001). Neopterin was positively correlated with kynurenine (kyn) (r=0.25, β=0.57, Plinear<0.001), the KTR (r=0.42, β=0.87, Plinear<0.001), 3-hydroxykynurenine (r=0.26, β=0.32, Plinear<0.001), anthranilic acid (r=0.29, β=0.36, Plinear<0.001), and quinolinic acid (QA) (r=0.41, β=0.56, Plinear<0.001). After a median follow-up of 3.2 years for OS, 14% (141) patients deceased. While patients with ‘high neopterin’ levels had a 43% increased risk of death (HR, 1.43, 95%CI 0.95-2.16), the ‘high kyn/high neopterin‘ patient group had a 52% increased risk of death (HR, 1.52, 95%CI 1.04-2.22). Similarly, the ‘high QA/high neopterin‘ and ‘high KTR/high neopterin‘ patient groups had a 85% and 89% increased risk of death, respectively (HRQA/Neopt, 1.85, 95%CI 1.24-2.75, HRKTR/Neopt, 1.89, 95%CI 1.27-2.80). Conclusion: Tryptophan-kynurenine pathway activation correlates with inflammation marker neopterin in CRC. Combined associations of kynurenine metabolites and neopterin may be a promising predictor for OS among stage I-III CRC patients. Citation Format: Victoria Damerell, Eline H. van Roekel, Stefanie Brezina, Dieuwertje E. Kok, Tengda Lin, Daniëlle D. Holthuijsen, Jennifer Ose, Caroline Himbert, Simone J. P. Eussen, Arve Ulvik, Fränzel J. van Duijnhoven, Jane C. Figueiredo, Christopher I. Li, Erin M. Siegel, Martin Schneider, David Shibata, Adetunji A. Toriola, Alexis B. Ulrich, Per M. Ueland, Matty P. Weijenberg, Andrea Gsur, Ellen Kampman, Cornelia M. Ulrich, Biljana Gigic. Associations of circulating levels of tryptophan-kynurenine metabolites and inflammation biomarker neopterin with overall survival among patients with stage I-III colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3421.

Background and AimsCardiorespiratory fitness has been postulated to lower chronic inflammation in obesity. We assessed sex-specific associations of inflammation with cardiorespiratory fitness in overweight and obese persons.Methods and ResultsPeak oxygen uptake (VO2max) was measured by treadmill in 566 participants (age 48±9 years, 60% women) with body mass index >27.0 kg/m2 in the FAT associated CardiOvasculaR dysfunction (FATCOR) study. Fitness was identified from age- and sex specific reference levels of VO2max. The inflammatory markers C-reactive protein (CRP), serum amyloid A (SAA), kynurenine:tryptophan ratio (KTR) and pyriodoxic acid ratio (PAr) were measured by mass spectrometry. In the total study population 63% had obesity and 74% were cardiorespiratory unfit. Unfit women had the highest fat percentage and the highest serum levels of CRP and SAA (p<0.05). In multivariable linear regression analyses in women, higher CRP (β -0.15, p=0.001), SAA (β -0.10, p=0.03) and PAr (β -0.09, p=0.03) were associated with lower VO2max after adjusting for confounders. In multivariable analyses in men, higher PAr (β -0.14, p=0.02) was associated with lower VO2max. In multivariable analyses in obese women, higher CRP and PAr remained associated with lower VO2max (p<0.05), while in obese men there was no significant association. When normalizing VO2max for fat-free mass (VO2maxFFM) higher CRP, SAA and PAr index were associated with lower VO2maxFFM in women, while only higher PAr index was associated with lower VO2maxFFM in men.ConclusionThe association of inflammation with lower cardiorespiratory fitness was more pronounced in women than men, in particular when obesity was present.Clinical trial registrationURL: http://www.clinicaltrials.gov NCT02805478.