Analyses of cerebrospinal fluid (CSF) metabolites in large, healthy samples have been limited and potential demographic moderators of brain metabolism are largely unknown.
Our objective in this study was to examine sex and race differences in 33 CSF metabolites within a sample of 129 healthy individuals (37 African American women, 29 white women, 38 African American men, and 25 white men).
CSF metabolites were measured with a targeted electrochemistry-based metabolomics platform. Sex and race differences were quantified with both univariate and multivariate analyses. Type I error was controlled for by using a Bonferroni adjustment (0.05/33 = .0015).
Multivariate Canonical Variate Analysis (CVA) of the 33 metabolites showed correct classification of sex at an average rate of 80.6% and correct classification of race at an average rate of 88.4%. Univariate analyses revealed that men had significantly higher concentrations of cysteine (p < 0.0001), uric acid (p < 0.0001), and N-acetylserotonin (p = 0.049), while women had significantly higher concentrations of 5-hydroxyindoleacetic acid (5-HIAA) (p = 0.001). African American participants had significantly higher concentrations of 3-hydroxykynurenine (p = 0.018), while white participants had significantly higher concentrations of kynurenine (p < 0.0001), indoleacetic acid (p < 0.0001), xanthine (p = 0.001), alpha-tocopherol (p = 0.007), cysteine (p = 0.029), melatonin (p = 0.036), and 7-methylxanthine (p = 0.037). After the Bonferroni adjustment, the effects for cysteine, uric acid, and 5-HIAA were still significant from the analysis of sex differences and kynurenine and indoleacetic acid were still significant from the analysis of race differences.
Several of the metabolites assayed in this study have been associated with mental health disorders and neurological diseases. Our data provide some novel information regarding normal variations by sex and race in CSF metabolite levels within the tryptophan, tyrosine and purine pathways, which may help to enhance our understanding of mechanisms underlying sex and race differences and potentially prove useful in the future treatment of disease.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
The metabolomics data reported in this study is available upon request to the corresponding author, Anastasia Georgiades.
Asberg, M., Bertilsson, L., Martensson, B., Scalia-Tomba, G. P., Thoren, P., & Traskman-Bendz, L. (1984). CSF monoamine metabolites in melancholia. Acta Psychiatrica Scandinavica, 69, 201–219. https://doi.org/10.1111/j.1600-0447.1984.tb02488.x.
Berger, P. A., et al. (1980). CSF monoamine metabolites in depression and schizophrenia. American Journal of Psychiatry, 137, 174–180. https://doi.org/10.1176/ajp.137.2.174.
Betz, A. L. (1985). Identification of hypoxanthine transport and xanthine oxidase activity in brain capillaries. Journal of Neurochemistry, 44, 574–579. https://doi.org/10.1111/j.1471-4159.1985.tb05451.x.
Blennow, K., et al. (1993). Cerebrospinal fluid monoamine metabolites in 114 healthy individuals 18–88 years of age. European Neuropsychopharmacology, 3, 55–61. https://doi.org/10.1016/0924-977x(93)90295-w.
Blom, H. J., & Smulders, Y. (2011). Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. Journal of Inherited Metabolic Disease, 34, 75–81. https://doi.org/10.1007/s10545-010-9177-4.
Bouckoms, A. J., et al. (1992). Monoamines in the brain cerebrospinal fluid of facial pain patients. Anesthesia Progress, 39, 201–208.
Brewerton, T. D., Putnam, K. T., Lewine, R. R. J., & Risch, S. C. (2018). Seasonality of cerebrospinal fluid monoamine metabolite concentrations and their associations with meteorological variables in humans. Journal of Psychiatric Research, 99, 76–82. https://doi.org/10.1016/j.jpsychires.2018.01.004.
Bridge, T. P., Soldo, B. J., Phelps, B. H., Wise, C. D., Francak, M. J., & Wyatt, R. J. (1985). Platelet monoamine oxidase activity: demographic characteristics contribute to enzyme activity variability. J Gerontol, 40, 23–28. https://doi.org/10.1093/geronj/40.1.23.
Cascalheira, J. F., et al. (2009). Serum homocysteine: interplay with other circulating and genetic factors in association to Alzheimer’s type dementia. Clinical Biochemistry, 42, 783–790. https://doi.org/10.1016/j.clinbiochem.2009.02.006.
Chen, Y., & Guillemin, G. J. (2009). Kynurenine pathway metabolites in humans: disease and healthy States. Int J Tryptophan Res, 2, 1–19. https://doi.org/10.4137/ijtr.s2097.
Colin-Gonzalez, A. L., Maldonado, P. D., & Santamaria, A. (2013). 3-Hydroxykynurenine: An intriguing molecule exerting dual actions in the central nervous system. Neurotoxicology, 34, 189–204. https://doi.org/10.1016/j.neuro.2012.11.007.
Condray, R., et al. (2011). 3-Hydroxykynurenine and clinical symptoms in first-episode neuroleptic-naive patients with schizophrenia. International Journal of Neuropsychopharmacology, 14, 756–767. https://doi.org/10.1017/S1461145710001689.
De Bellis, M. D., Geracioti, T. D., Jr., Altemus, M., & Kling, M. A. (1993). Cerebrospinal fluid monoamine metabolites in fluoxetine-treated patients with major depression and in healthy volunteers. Biological Psychiatry, 33, 636–641. https://doi.org/10.1016/0006-3223(93)90103-k.
Dou, L., et al. (2015). The cardiovascular effect of the uremic solute indole-3 acetic acid. Journal of the American Society of Nephrology, 26, 876–887. https://doi.org/10.1681/ASN.2013121283.
Droge, W. (2005). Oxidative stress and ageing: is ageing a cysteine deficiency syndrome? Philosophical Transactions of the Royal Society B-Biological Sciences, 360, 2355–2372. https://doi.org/10.1098/rstb.2005.1770.
Ehnvall, A., Sjogren, M., Zachrisson, O. C., & Agren, H. (2003). Lifetime burden of mood swings and activation of brain norepinephrine turnover in patients with treatment-refractory depressive illness. Journal of Affective Disorders, 74, 185–189. https://doi.org/10.1016/s0165-0327(02)00011-3.
Fukagawa, N. K., Martin, J. M., Wurthmann, A., Prue, A. H., Ebenstein, D., & O’Rourke, B. (2000). Sex-related differences in methionine metabolism and plasma homocysteine concentrations. American Journal of Clinical Nutrition, 72, 22–29. https://doi.org/10.1093/ajcn/72.1.22.
Geracioti, T. D., Jr., et al. (1997). Uncoupling of serotonergic and noradrenergic systems in depression: Preliminary evidence from continuous cerebrospinal fluid sampling. Depress Anxiety, 6, 89–94.
Gerner, R. H., et al. (1984). Csf neurochemistry in depressed, manic, and schizophrenic-patients compared with that of normal controls. American Journal of Psychiatry, 141, 1533–1540.
Goudas, L. C., et al. (1999). Acute decreases in cerebrospinal fluid glutathione levels after intracerebroventricular morphine for cancer pain. Anesthesia and Analgesia, 89, 1209–1215.
Heafield, M. T., Fearn, S., Steventon, G. B., Waring, R. H., Williams, A. C., & Sturman, S. G. (1990). Plasma cysteine and sulphate levels in patients with motor neurone, Parkinson’s and Alzheimer’s disease. Neuroscience Letters, 110, 216–220. https://doi.org/10.1016/0304-3940(90)90814-p.
Hou, C. L., Jia, F. J., Liu, Y., & Li, L. J. (2006). CSF serotonin, 5-hydroxyindolacetic acid and neuropeptide Y levels in severe major depressive disorder. Brain Research, 1095, 154–158. https://doi.org/10.1016/j.brainres.2006.04.026.
Jones, J. S., et al. (1990). Csf 5-Hiaa and Hva concentrations in elderly depressed-patients who attempted-suicide. American Journal of Psychiatry, 147, 1225–1227.
Jones, R. S. (1982). Tryptamine: A neuromodulator or neurotransmitter in mammalian brain? Progress in Neurobiology, 19, 117–139. https://doi.org/10.1016/0301-0082(82)90023-5.
Kaddurah-Daouk, R., et al. (2011). Metabolomic changes in autopsy-confirmed Alzheimer’s disease. Alzheimers Dement, 7, 309–317. https://doi.org/10.1016/j.jalz.2010.06.001.
Kaddurah-Daouk, R., et al. (2012). Cerebrospinal fluid metabolome in mood disorders-remission state has a unique metabolic profile. Sci Rep, 2, 667. https://doi.org/10.1038/srep00667.
Kaddurah-Daouk, R., et al. (2013). Alterations in metabolic pathways and networks in Alzheimer’s disease. Transl Psychiatry, 3, e244. https://doi.org/10.1038/tp.2013.18.
Kasa, K., Otsuki, S., Yamamoto, M., Sato, M., Kuroda, H., & Ogawa, N. (1982). Cerebrospinal-fluid gamma-aminobutyric acid and homovanillic-acid in depressive-disorders. Biological Psychiatry, 17, 877–883.
Kegel, M. E., et al. (2014). Imbalanced kynurenine pathway in schizophrenia. International Journal of Tryptophan Research, 7, 15–22. https://doi.org/10.4137/IJTR.S16800.
Kim, Y. S., Unno, T., Kim, B. Y., & Park, M. S. (2019). Sex Differences in Gut Microbiota. World Journal of Mens Health. https://doi.org/10.5534/wjmh.190009.
Koslow, S. H., Maas, J. W., Bowden, C. L., Davis, J. M., Hanin, I., & Javaid, J. (1983). Csf and urinary biogenic-amines and metabolites in depression and mania—a controlled, univariate analysis. Archives of General Psychiatry, 40, 999–1010.
Krause, D., et al. (2011). The tryptophan metabolite 3-hydroxyanthranilic acid plays anti-inflammatory and neuroprotective roles during inflammation: role of hemeoxygenase-1. American Journal of Pathology, 179, 1360–1372. https://doi.org/10.1016/j.ajpath.2011.05.048.
Kristal, B. S., Shurubor, Y. I., Kaddurah-Daouk, R., & Matson, W. R. (2007). High-performance liquid chromatography separations coupled with coulometric electrode array detectors: a unique approach to metabolomics. Methods in Molecular Biology, 358, 159–174. https://doi.org/10.1007/978-1-59745-244-1_10.
Kristal, B. S., Vigneau-Callahan, K., & Matson, W. R. (2002). Simultaneous analysis of multiple redox-active metabolites from biological matrices. Methods in Molecular Biology, 186, 185–194. https://doi.org/10.1385/1-59259-173-6:185.
Kristal, B. S., Vigneau-Callahan, K. E., & Matson, W. R. (1998). Simultaneous analysis of the majority of low-molecular-weight, redox-active compounds from mitochondria. Analytical Biochemistry, 263, 18–25. https://doi.org/10.1006/abio.1998.2831.
Lewerenz, J., et al. (2013). The cystine/glutamate antiporter system x(c)(-) in health and disease: From molecular mechanisms to novel therapeutic opportunities. Antioxidants & Redox Signaling, 18, 522–555. https://doi.org/10.1089/ars.2011.4391.
LeWitt, P. A., et al. (1992). Markers of dopamine metabolism in Parkinson’s disease. The Parkinson Study Group. Neurology, 42, 2111–2117. https://doi.org/10.1212/wnl.42.11.2111.
Little, J. T., Ketter, T. A., Mathe, A. A., Frye, M. A., Luckenbaugh, D., & Post, R. M. (1999). Venlafaxine but not bupropion decreases cerebrospinal fluid 5-hydroxyindoleacetic acid in unipolar depression. Biological Psychiatry, 45, 285–289. https://doi.org/10.1016/s0006-3223(98)00078-x.
Liu, B., Shen, Y., Xiao, K., Tang, Y., Cen, L., & Wei, J. (2012). Serum uric acid levels in patients with multiple sclerosis: a meta-analysis. Neurological Research, 34, 163–171. https://doi.org/10.1179/1743132811Y.0000000074.
Liu, D., et al. (2018). Beta-defensin 1, aryl hydrocarbon receptor and plasma kynurenine in major depressive disorder: metabolomics-informed genomics. Transl Psychiatry, 8, 10. https://doi.org/10.1038/s41398-017-0056-8.
Lucot, J. B., Crampton, G. H., Matson, W. R., & Gamache, P. H. (1989). Cerebrospinal fluid constituents of cat vary with susceptibility to motion sickness. Life Sciences, 44, 1239–1245. https://doi.org/10.1016/0024-3205(89)90359-7.
Matson, W. R., Langlais, P., Volicer, L., Gamache, P. H., Bird, E., & Mark, K. A. (1984). n-Electrode three-dimensional liquid chromatography with electrochemical detection for determination of neurotransmitters. Clinical Chemistry, 30, 1477–1488.
Molchan, S. E., et al. (1991). CSF monoamine metabolites and somatostatin in Alzheimer’s disease and major depression. Biological Psychiatry, 29, 1110–1118. https://doi.org/10.1016/0006-3223(91)90253-i.
Murphy, D. L., Wright, C., Buchsbaum, M., Nichols, A., Costa, J. L., & Wyatt, R. J. (1976). Platelet and plasma amine oxidase activity in 680 normals—sex and age-differences and stability over time. Biochemical Medicine, 16, 254–265. https://doi.org/10.1016/0006-2944(76)90031-4.
Nagata, Y., et al. (2018). Comparative analysis of cerebrospinal fluid metabolites in Alzheimer’s disease and idiopathic normal pressure hydrocephalus in a Japanese cohort. Biomark Research, 6, 5. https://doi.org/10.1186/s40364-018-0119-x.
Nilsson, L. K., Nordin, C., Jonsson, E. G., Engberg, G., Linderholm, K. R., & Erhardt, S. (2007). Cerebrospinal fluid kynurenic acid in male and female controls—Correlation with monoamine metabolites and influences of confounding factors. Journal of Psychiatric Research, 41, 144–151. https://doi.org/10.1016/j.jpsychires.2005.12.001.
Nørgaard, L., Bro, R., Westad, F., & Engelsen, S. B. (2006). A modification of canonical variates analysis to handle highly collinear multivariate data. Journal of Chemometrics, 20, 425–435.
O’Mahony, S. M., Clarke, G., Borre, Y. E., Dinan, T. G., & Cryan, J. F. (2015). Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behavioural Brain Research, 277, 32–48. https://doi.org/10.1016/j.bbr.2014.07.027.
Olivola, E., et al. (2014). Serotonin impairment in CSF of PD patients, without an apparent clinical counterpart. PLoS ONE, 9, e101763. https://doi.org/10.1371/journal.pone.0101763.
Oreland, L., et al. (1981). Platelet MAO activity and monoamine metabolites in cerebrospinal fluid in depressed and suicidal patients and in healthy controls. Psychiatry Research, 4, 21–29. https://doi.org/10.1016/0165-1781(81)90004-4.
Paganoni, S., et al. (2012). Uric acid levels predict survival in men with amyotrophic lateral sclerosis. Journal of Neurology, 259, 1923–1928. https://doi.org/10.1007/s00415-012-6440-7.
Palaniappun, V., Ramachandran, V., & Somasundaram, O. (1991). Norepinephrine and serotonin metabolism and clinical response to combined imipramine and amitriptyline therapy in depression. Indian Journal of Psychiatry, 33, 193–199.
Petersen, A. K., et al. (2012). On the hypothesis-free testing of metabolite ratios in genome-wide and metabolome-wide association studies. BMC Bioinformatics, 13, 120. https://doi.org/10.1186/1471-2105-13-120.
Post, R. M., Gordon, E. K., Goodwin, F. K., & Bunney, W. E., Jr. (1973). Central norepinephrine metabolism in affective illness: MHPG in the cerebrospinal fluid. Science, 179, 1002–1003. https://doi.org/10.1126/science.179.4077.1002.
Reddy, P. L., Khanna, S., Subhash, M. N., Channabasavanna, S. M., & Rao, B. S. (1992). CSF amine metabolites in depression. Biological Psychiatry, 31, 112–118. https://doi.org/10.1016/0006-3223(92)90198-9.
Reus, G. Z., Jansen, K., Titus, S., Carvalho, A. F., Gabbay, V., & Quevedo, J. (2015). Kynurenine pathway dysfunction in the pathophysiology and treatment of depression: Evidences from animal and human studies. Journal of Psychiatric Research, 68, 316–328. https://doi.org/10.1016/j.jpsychires.2015.05.007.
Roy, A., et al. (1986). Reduced CSF concentrations of homovanillic acid and homovanillic acid to 5-hydroxyindoleacetic acid ratios in depressed patients: relationship to suicidal behavior and dexamethasone nonsuppression. American Journal of Psychiatry, 143, 1539–1545. https://doi.org/10.1176/ajp.143.12.1539.
Roy, A., Pickar, D., De Jong, J., Karoum, F., & Linnoila, M. (1988). Norepinephrine and its metabolites in cerebrospinal fluid, plasma, and urine. Relationship to hypothalamic-pituitary-adrenal axis function in depression. Archives of General Psychiatry, 45, 849–857. https://doi.org/10.1001/archpsyc.1988.01800330081010.
Roy, A., Pickar, D., De Jong, J., Karoum, F., & Linnoila, M. (1989). Suicidal behavior in depression: relationship to noradrenergic function. Biological Psychiatry, 25, 341–350. https://doi.org/10.1016/0006-3223(89)90181-9.
Rozen, S., et al. (2005). Metabolomic analysis and signatures in motor neuron disease. Metabolomics, 1, 101–108. https://doi.org/10.1007/s11306-005-4810-1.
Savitz, J., et al. (2015). Neuroprotective kynurenine metabolite indices are abnormally reduced and positively associated with hippocampal and amygdalar volume in bipolar disorder. Psychoneuroendocrinology, 52, 200–211. https://doi.org/10.1016/j.psyneuen.2014.11.015.
Sher, L., et al. (2006). Lower cerebrospinal fluid homovanillic acid levels in depressed suicide attempters. Journal of Affective Disorders, 90, 83–89. https://doi.org/10.1016/j.jad.2005.10.002.
Sher, L., et al. (2005). Higher cerebrospinal fluid homovanillic acid levels in depressed patients with comorbid posttraumatic stress disorder. European Neuropsychopharmacology, 15, 203–209. https://doi.org/10.1016/j.euroneuro.2004.09.009.
Sher, L., et al. (2003). Lower CSF homovanillic acid levels in depressed patients with a history of alcoholism. Neuropsychopharmacology, 28, 1712–1719. https://doi.org/10.1038/sj.npp.1300231.
Shi, H., Vigneau-Callahan, K. E., Matson, W. R., & Kristal, B. S. (2002). Attention to relative response across sequential electrodes improves quantitation of coulometric array. Analytical Biochemistry, 302, 239–245. https://doi.org/10.1006/abio.2001.5568.
Shurubor, Y. I., Matson, W. R., Martin, R. J., & Kristal, B. S. (2005). Relative contribution of specific sources of systematic errors and analytical imprecision to metabolite analysis by HPLC–ECD. Metabolomics, 1, 159–168. https://doi.org/10.1007/s11306-005-4431-8.
Stover, J. F., Lowitzsch, K., & Kempski, O. S. (1997). Cerebrospinal fluid hypoxanthine, xanthine and uric acid levels may reflect glutamate-mediated excitotoxicity in different neurological diseases. Neuroscience Letters, 238, 25–28. https://doi.org/10.1016/S0304-3940(97)00840-9.
Sullivan, G. M., Mann, J. J., Oquendo, M. A., Lo, E. S., Cooper, T. B., & Gorman, J. M. (2006a). Low cerebrospinal fluid transthyretin levels in depression: correlations with suicidal ideation and low serotonin function. Biological Psychiatry, 60, 500–506. https://doi.org/10.1016/j.biopsych.2005.11.022.
Sullivan, G. M., Oquendo, M. A., Huang, Y. Y., & Mann, J. J. (2006b). Elevated cerebrospinal fluid 5-hydroxyindoleacetic acid levels in women with comorbid depression and panic disorder. International Journal of Neuropsychopharmacology, 9, 547–556. https://doi.org/10.1017/S1461145705006231.
Swann, A. C., Katz, M. M., Bowden, C. L., Berman, N. G., & Stokes, P. E. (1999). Psychomotor performance and monoamine function in bipolar and unipolar affective disorders. Biological Psychiatry, 45, 979–988. https://doi.org/10.1016/s0006-3223(98)00172-3.
Tabunoki, H., et al. (2013). Identification of key uric acid synthesis pathway in a unique mutant silkworm Bombyx mori model of Parkinson’s disease. PLoS ONE, 8, e69130. https://doi.org/10.1371/journal.pone.0069130.
Vanholder, R., Pletinck, A., Schepers, E., & Glorieux, G. (2018). Biochemical and clinical impact of organic uremic retention solutes: A comprehensive update. Toxins (Basel),. https://doi.org/10.3390/toxins10010033.
Volicer, L., Langlais, P. J., Matson, W. R., Mark, K. A., & Gamache, P. H. (1985). Serotoninergic system in dementia of the Alzheimer type: abnormal forms of 5-hydroxytryptophan and serotonin in cerebrospinal fluid. Archives of Neurology, 42, 1158–1161. https://doi.org/10.1001/archneur.1985.04060110040013.
Westenberg, H. G., & Verhoeven, W. M. (1988). CSF monoamine metabolites in patients and controls: Support for a bimodal distribution in major affective disorders. Acta Psychiatrica Scandinavica, 78, 541–549. https://doi.org/10.1111/j.1600-0447.1988.tb06382.x.
Widerlov, E., Bissette, G., & Nemeroff, C. B. (1988). Monoamine metabolites, corticotropin releasing-factor and somatostatin as Csf markers in depressed-patients. Journal of Affective Disorders, 14, 99–107. https://doi.org/10.1016/0165-0327(88)90051-1.
Williams, R. B., et al. (2003). Serotonin-related gene polymorphisms and central nervous system serotonin function. Neuropsychopharmacology, 28, 533–541. https://doi.org/10.1038/sj.npp.1300054.
Yoon, H. S., et al. (2017). Relationships of cerebrospinal fluid monoamine metabolite levels with clinical variables in major depressive disorder. Journal of Clinical Psychiatry, 78, e947–e956. https://doi.org/10.4088/JCP.16m11144.
Young, S. N., Anderson, G. M., Gauthier, S., & Purdy, W. C. (1980a). The origin of indoleacetic acid and indolepropionic acid in rat and human cerebrospinal fluid. Journal of Neurochemistry, 34, 1087–1092. https://doi.org/10.1111/j.1471-4159.1980.tb09944.x.
Young, S. N., Anderson, G. M., & Purdy, W. C. (1980b). Indoleamine metabolism in rat brain studied through measurements of tryptophan, 5-hydroxyindoleacetic acid, and indoleacetic acid in cerebrospinal fluid. Journal of Neurochemistry, 34, 309–315. https://doi.org/10.1111/j.1471-4159.1980.tb06598.x.
The research in this manuscript was funded by the NHLBI Grant Number P01-HL036587.
Conflict of interest
Redford Williams holds a U.S. patent on the use of 5HTTLPR L allele as a marker of increased cardiovascular disease risk. The remaining authors have nothing to disclose.
The study was approved by the Duke University Medical Center Institutional Review Board.
Consent to participate
The present study was conducted at Duke University Medical Center, and all subjects gave informed consent prior to their participation in the study using a consent form approved by the Duke University Medical Center Institutional Review Board.
Consent for publication
Not applicable (the results presented contain no identifiable information).
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Below is the link to the electronic supplementary material.
About this article
Cite this article
Reavis, Z.W., Mirjankar, N., Sarangi, S. et al. Sex and race differences of cerebrospinal fluid metabolites in healthy individuals. Metabolomics 17, 13 (2021). https://doi.org/10.1007/s11306-020-01757-0
- Cerebrospinal fluid
- Monoamine metabolites
- 5-Hydroxyindoleacetic acid
- Tryptophan pathway
- Tyrosine pathway
- Purine pathway
- Central nervous system