CoChat
Sign Up
Cited by 37Tryptophan and brain disordersAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

Correlations between kynurenines in plasma and CSF, and their relation to markers of Alzheimer's disease pathology

Open access
Bakker, Lieke, Köhler, Sebastian, Eussen, Simone J.P.M., Choe, Kyonghwan, van den Hove, Daniel L.A., Kenis, Gunter, Rutten, Bart P.F., Ulvik, Arve +3 more·2023·Brain, Behavior, and Immunity
DOI 10.1016/j.bbi.2023.04.015
Open this paper in CoChat — free accountOpen PDF

Abstract

Introduction Altered levels of kynurenines in blood and cerebrospinal fluid (CSF) have been reported in Alzheimer's disease (AD). However, it is still largely unknown whether peripheral kynurenine concentrations resemble those found in CSF and how they relate to AD pathology. We therefore studied correlations between kynurenines in plasma and CSF and their associations with CSF amyloid-beta (Aβ 1-42) and tau levels in patients from the memory clinic spanning the whole cognitive spectrum. Methods The Biobank Alzheimer Center Limburg study is a prospective cohort study of consecutive patients referred to the memory clinic of the Alzheimer Center Limburg. Plasma and CSF concentrations of tryptophan (TRP), eight kynurenines and neopterin from 138 patients were determined by means of LC-MS/MS. Additionally, CSF Aβ 1-42, total-tau (t-tau) and phosphorylated tau (p-tau) concentrations were determined using commercially available single-parameter ELISA methods. Partial correlations were used to analyze cross-sectional associations between kynurenines in plasma and CSF and their relation to AD related CSF-biomarkers adjusted for age, sex, educational level, and kidney function. Results Moderate to strong correlations were observed between plasma and CSF levels for quinolinic acid (QA; r = 0.63), TRP (r = 0.47), anthranilic acid (r = 0.59), picolinic acid (r = 0.55), and the kynurenine (KYN)/TRP ratio (KTR; r = 0.55; all p < 0.0001), while other kynurenines correlated only weakly with their corresponding CSF values. No correlations were found between plasma and CSF levels of KA/QA. Several kynurenines were also weakly correlated with Aβ 1-42, t-tau or p-tau. Plasma levels of KA/QA were negatively correlated with Aβ 1-42 (r = -0.21, p < 0.05). Plasma levels of TRP were negatively correlated with t-tau (r = -0.19) and levels of KYN with p-tau (r = -0.18; both p < 0.05). CSF levels of KYN (r = 0.20, p < 0.05), KA (r = 0.23, p < 0.01), and KTR (r = 0.18, p < 0.05) were positively correlated with Aβ 1-42. Finally, TRP and KYN were negatively (r = -0.22 and r = -0.18, respectively), and neopterin positively (r = 0.19) correlated with p-tau (all p < 0.05). Conclusions Plasma concentrations of TRP, KP metabolites, KTR, and neopterin all significantly correlated positively with their corresponding CSF concentrations, but many correlations were weak. Additionally, our results suggest a relation between higher kynurenine levels and lower AD pathology load. These results need verification in future studies and require more research into (shared) underlying mechanisms.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.bbi.2023.04.015

Cites

5 of 5 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Previous studies have evaluated protein correlations between plasma and CSF biomarkers of AD.

    “Previous studies have evaluated protein correlations between plasma and CSF biomarkers of AD. 37 , 38 , 39 , 40 , 41 , 42 , 43”

    From A genetic and proteomic comparison of key AD biomarkers across tissues (2024) · cites this paper as [37]

    The Statistical analysis section (2.3; page not provided) describes correlations between plasma and CSF kynurenines and between kynurenines and CSF Aβ and tau. Results section 3.3 reports associations between plasma metabolites and CSF AD markers, but the paper does not report correlations between protein biomarkers measured in both plasma and CSF. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 44

  1. Bakker, L., Ramakers, I.H.G.B., van Boxtel, M.P.J., Schram, M.T., Stehouwer, C.D.A., van der Kallen, C.J.H., Dagnelie, P.C., van Greevenbroek, M.M.J., Wesselius, A., Midttun, Ø., Ueland, P.M., Verhey, F.R.J., Eussen, S.J.P.M., Köhler, S., 2021. Associations between plasma kynurenines and cognitive function in individuals with normal glucose metabolism, prediabetes and type 2 diabetes: the Maastricht Study. Diabetologia 64 (11), 2445-2457.
  2. Berger, Z., Roder, H., Hanna, A., Carlson, A., Rangachari, V., Yue, M., Wszolek, Z., Ashe, K., Knight, J., Dickson, D., Andorfer, C., Rosenberry, T.L., Lewis, J., Hutton, M., Janus, C., 2007. Accumulation of pathological tau species and memory loss in a conditional model of tauopathy. J. Neurosci. 27 (14), 3650-3662.
  3. Bonda, D.J., Mailankot, M., Stone, J.G., Garrett, M.R., Staniszewska, M., Castellani, R.J., Siedlak, S.L., Zhu, X., Lee, H.-G., Perry, G., Nagaraj, R.H., Smith, M.A., 2010. Indoleamine 2,3-dioxygenase and 3-hydroxykynurenine modifications are found in the neuropathology of Alzheimer's disease. Redox Rep. 15 (4), 161-168.
  4. Carrillo-Mora, P., Méndez-Cuesta, L.A., Pérez-De La Cruz, V., Fortoul-van Der Goes, T.I., Santamaría, A., 2010. Protective effect of systemic L-kynurenine and probenecid administration on behavioural and morphological alterations induced by toxic soluble amyloid beta (25-35) in rat hippocampus. Behav. Brain Res. 210 (2), 240-250.
  5. Chatterjee, P., et al., 2019. Plasma neurofilament light chain and amyloid-beta are associated with the kynurenine pathway metabolites in preclinical Alzheimer's disease. J. Neuroinflammation 16 (1), 186.
  6. Darst, B.F., Koscik, R.L., Hogan, K.J., Johnson, S.C., Engelman, C.D., 2019. Longitudinal plasma metabolomics of aging and sex. Aging (Albany NY) 11 (4), 1262-1282.
  7. Folstein, M.F., Folstein, S.E., McHugh, P.R., 1975. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J. Psychiatr. Res. 12 (3), 189-198.
  8. Foster, A.C., Miller, L.P., Oldendorf, W.H., Schwarcz, R., 1984. Studies on the disposition of quinolinic acid after intracerebral or systemic administration in the rat. Exp. Neurol. 84 (2), 428-440.
  9. Fukui, S., Schwarcz, R., Rapoport, S.I., Takada, Y., Smith, Q.R., 1991. Blood-Brain- Barrier Transport of Kynurenines -Implications for Brain Synthesis and Metabolism. J. Neurochem. 56 (6), 2007-2017.
  10. Gal, E.M., Sherman, A.D., 1980. L-kynurenine: its synthesis and possible regulatory function in brain. Neurochem. Res. 5 (3), 223-239.
  11. Galasko, D., Montine, T.J., 2010. Biomarkers of oxidative damage and inflammation in Alzheimer's disease. Biomark. Med. 4 (1), 27-36.
  12. Giil, L.M., Midttun, Ø., Refsum, H., Ulvik, A., Advani, R., Smith, A.D., Ueland, P.M., 2017. Kynurenine Pathway Metabolites in Alzheimer's Disease. J. Alzheimers Dis. 60 (2), 495-504.
  13. González-Sánchez, M., Jiménez, J., Narváez, A., Antequera, D., Llamas-Velasco, S., Martín, A.-S., Molina Arjona, J.A., López de Munain, A., Lleó Bisa, A., Marco, M.-P., Rodríguez-Núñez, M., Pérez-Martínez, D.A., Villarejo-Galende, A., Bartolome, F., Domínguez, E., Carro, E., 2020. Kynurenic Acid Levels are Increased in the CSF of Alzheimer's Disease Patients. Biomolecules 10 (4), 571.
  14. Guillemin, G.J., 2012. Quinolinic acid, the inescapable neurotoxin. FEBS J. 279 (8), 1356-1365.
  15. Guillemin, G.J., Brew, B.J., Noonan, C.E., Takikawa, O., Cullen, K.M., 2005. Indoleamine 2,3 dioxygenase and quinolinic acid immunoreactivity in Alzheimer's disease hippocampus. Neuropathol. Appl. Neurobiol. 31 (4), 395-404.
  16. Gulaj, E., Pawlak, K., Bien, B., Pawlak, D., 2010. Kynurenine and its metabolites in Alzheimer's disease patients. Adv. Med. Sci. 55 (2), 204-211.
  17. Haroon, E., Welle, J.R., Woolwine, B.J., Goldsmith, D.R., Baer, W., Patel, T., Felger, J.C., Miller, A.H., 2020. Associations among peripheral and central kynurenine pathway metabolites and inflammation in depression. Neuropsychopharmacology 45 (6), 998-1007.
  18. Heyes, M.P., Morrison, P.F., 1997. Quantification of local de novo synthesis versus blood contributions to quinolinic acid concentrations in brain and systemic tissues. J. Neurochem. 68 (1), 280-288.
  19. Heyes, M.P., Brew, B.J., Martin, A., Price, R.W., Salazar, A.M., Sidtis, J.J., Yergey, J.A., Mouradian, M.M., Sadler, A.E., Keilp, J., Rubinow, D., Markey, S.P., 1991. Quinolinic acid in cerebrospinal fluid and serum in HIV-1 infection: relationship to clinical and neurological status. Ann. Neurol. 29 (2), 202-209.
  20. Heyes, M.P., Saito, K., Devinsky, O., Nadi, N.S., 1994. Kynurenine pathway metabolites in cerebrospinal fluid and serum in complex partial seizures. Epilepsia 35 (2), 251-257.
  21. Holthuijsen, D.D.B., Bours, M.J.L., Roekel, E.H.V., Breukink, S.O., Janssen-Heijnen, M.L. G., Keulen, E.T.P., Ueland, P.M., Midttun, Ø., Brezina, S., Gigic, B., Gsur, A., Kok, D. E., Ose, J., Ulrich, C.M., Weijenberg, M.P., Eussen, S.J.P.M., 2022. Longitudinal Associations of Adherence to the Dietary World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) and Dutch Healthy Diet (DHD) Recommendations with Plasma Kynurenines in Colorectal Cancer Survivors after Treatment. Nutrients 14 (23), 5151.
  22. Ittner, L.M., et al., 2010. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell 142 (3), 387-397.
  23. Jansen, W.J., et al., 2015. Prevalence of cerebral amyloid pathology in persons without dementia A meta-analysis. JAMA-J. Am. Med. Assoc. 313 (19), 1924.
  24. Janssens, J., Vermeiren, Y., van Faassen, M., van der Ley, C., Kema, I.P., De Deyn, P.P., 2020. Monoaminergic and Kynurenergic Characterization of Frontotemporal Dementia and Amyotrophic Lateral Sclerosis in Cerebrospinal Fluid and Serum. Neurochem. Res. 45 (5), 1191-1201.
  25. Jha, S.K., Jha, N.K., Kumar, D., Ambasta, R.K., Kumar, P., 2017. Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration. Biochim. Biophys. Acta Mol. basis Dis. 1863 (5), 1132-1146.
  26. Kincses, Z.T., Toldi, J., Vecsei, L., 2010. Kynurenines, neurodegeneration and Alzheimer's disease. J. Cell Mol. Med. 14 (8), 2045-2054.
  27. Kita, T., Morrison, P.F., Heyes, M.P., Markey, S.P., 2002. Effects of systemic and central nervous system localized inflammation on the contributions of metabolic precursors to the L-kynurenine and quinolinic acid pools in brain. J. Neurochem. 82 (2), 258-268.
  28. Kitt, T.M., Spector, R., 1987. Transport of quinolinic acid into rabbit and rat brain. Neurochem. Res. 12 (7), 625-628.
  29. Levey, A.S., Stevens, L.A., Schmid, C.H., Zhang, Y.(., Castro, A.F., Feldman, H.I., Kusek, J. W., Eggers, P., Van Lente, F., Greene, T., Coresh, J., 2009. A new equation to estimate glomerular filtration rate. Ann. Intern. Med. 150 (9), 604.
  30. Li, S.X., Hodge, A.M., MacInnis, R.J., Bassett, J.K., Ueland, P.M., Midttun, Ø., Ulvik, A., Rinaldi, S., Meyer, K., Navionis, A.-S., Shivappa, N., Hébert, J.R., Flicker, L., Severi, G., Jayasekara, H., English, D.R., Vineis, P., Southey, M.C., Milne, R.L., Giles, G.G., Dugué, P.-A., 2021. Inflammation-related marker profiling of dietary patterns and all-cause mortality in the melbourne collaborative cohort study. J. Nutr. 151 (10), 2908-2916.
  31. Morris, J.C., 1993. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 43 (11), 2412-2414.
  32. Mourdian, M.M., Heyes, M.P., Pan, J.-B., Heuser, I.J.E., Markey, S.P., Chase, T.N., 1989. No changes in central quinolinic acid levels in Alzheimer's disease. Neurosci. Lett. 105 (1-2), 233-238.
  33. Rahman, A., Ting, K., Cullen, K.M., Braidy, N., Brew, B.J., Guillemin, G.J., Egles, C., 2009. The excitotoxin quinolinic acid induces tau phosphorylation in human neurons. PLoS One 4 (7), e6344.
  34. Rocher, A.B., Crimins, J.L., Amatrudo, J.M., Kinson, M.S., Todd-Brown, M.A., Lewis, J., Luebke, J.I., 2010. Structural and functional changes in tau mutant mice neurons are not linked to the presence of NFTs. Exp. Neurol. 223 (2), 385-393.
  35. Saito, K., Crowley, J.S., Markey, S.P., Heyes, M.P., 1993. A Mechanism for Increased Quinolinic Acid Formation Following Acute Systemic Immune Stimulation. J. Biol. Chem. 268 (21), 15496-15503.
  36. SantaCruz, K., Lewis, J., Spires, T., Paulson, J., Kotilinek, L., Ingelsson, M., Guimaraes, A., DeTure, M., Ramsden, M., McGowan, E., Forster, C., Yue, M., Orne, J., Janus, C., Mariash, A., Kuskowski, M., Hyman, B., Hutton, M., Ashe, K.H., 2005. Tau suppression in a neurodegenerative mouse model improves memory function. Science 309 (5733), 476-481.
  37. Savitz, J., 2020. The kynurenine pathway: a finger in every pie. Mol. Psychiatry 25 (1), 131-147.
  38. Schlittler, M., Goiny, M., Agudelo, L.Z., Venckunas, T., Brazaitis, M., Skurvydas, A., Kamandulis, S., Ruas, J.L., Erhardt, S., Westerblad, H., Andersson, D.C., 2016. Endurance exercise increases skeletal muscle kynurenine aminotransferases and plasma kynurenic acid in humans. Am. J. Physiol. Cell Physiol. 310 (10), C836-C840.
  39. Sharma, R., Razdan, K., Bansal, Y., Kuhad, A., 2018. Rollercoaster ride of kynurenines: steering the wheel towards neuroprotection in Alzheimer's disease. Expert Opin. Ther. Targets 22 (10), 849-867.
  40. Skorobogatov, K., De Picker, L., Verkerk, R., Coppens, V., Leboyer, M., Müller, N., Morrens, M., 2021. Brain Versus Blood: A Systematic Review on the Concordance Between Peripheral and Central Kynurenine Pathway Measures in Psychiatric Disorders. Front. Immunol. 12.
  41. Sorgdrager, F.J.H., Vermeiren, Y., Faassen, M., Ley, C., Nollen, E.A.A., Kema, I.P., De Deyn, P.P., 2019. Age-and disease-specific changes of the kynurenine pathway in Parkinson's and Alzheimer's disease. J. Neurochem. 151 (5), 656-668.
  42. Theofylaktopoulou, D., Midttun, Ø., Ulvik, A., Ueland, P.M., Tell, G.S., Vollset, S.E., Nygård, O., Eussen, S.J.P.M., 2013. A community-based study on determinants of circulating markers of cellular immune activation and kynurenines: the Hordaland Health Study. Clin. Exp. Immunol. 173 (1), 121-130.
  43. Vécsei, L., Szalárdy, L., Fülöp, F., Toldi, J., 2013. Kynurenines in the CNS: recent advances and new questions. Nat. Rev. Drug Discov. 12 (1), 64-82.
  44. Zwilling, D., Huang, S.-Y., Sathyasaikumar, K., Notarangelo, F., Guidetti, P., Wu, H.-Q., Lee, J., Truong, J., Andrews-Zwilling, Y., Hsieh, E., Louie, J., Wu, T., Scearce- Levie, K., Patrick, C., Adame, A., Giorgini, F., Moussaoui, S., Laue, G., Rassoulpour, A., Flik, G., Huang, Y., Muchowski, J., Masliah, E., Schwarcz, R., Muchowski, P., 2011. Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell 145 (6), 863-874.

Cited by

Sorted by citations

Authors
Bakker, L., Köhler, S., Eussen, S. J. P. M., Choe, K., van den Hove, D. L. A., Kenis, G., Rutten, B. P. F., Ulvik, A., Ueland, P. M., Verhey, F. R. J., & Ramakers, I. H. G. B.
Affiliations
  • Maastricht University (NL)
  • Bevital (Norway) (NO)
Corresponding author
Ramakers, Inez H.G.B.
ORCID
Venue
Brain, Behavior, and Immunity
Publisher
Elsevier BV
Published
2023-07
Volume
111
Pages
312-319
ISSN
0889-1591 (ISSN-L)
DOI
10.1016/j.bbi.2023.04.015
OpenAlex
W4368347740
Cited by
37
References
5
Citations by year
2026: 12 · 2025: 14 · 2024: 8 · 2023: 3
FWCI
3.28
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain Behavior and Immunity (publishedVersion)
  • PubMed (publishedVersion)
  • Research Publications (Maastricht University) (submittedVersion, other-oa)
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
kynurenine, plasma, cerebrospinal fluid, Alzheimer's disease, tryptophan metabolism, quinolinic acid, kynurenine/tryptophan ratio, amyloid-beta 42, tau phosphorylation, neopterin, biomarkers, peripheral biomarkers, cerebrospinal fluid biomarkers, kynurenine pathway, memory clinic patients
MeSH terms
Alzheimer Disease, Chromatography, Liquid, Cross-Sectional Studies, Humans, Kynurenine, Prospective Studies, Tryptophan, Biomarkers, Amyloid beta-Peptides, tau Proteins, Neopterin, Tandem Mass Spectrometry

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review