Luke Whiley1,2,3, Katie E Chappell4,5, Ellie D'Hondt6, Matthew R Lewis4,5, Beatriz Jiménez5, Stuart G Snowden7,8, Hilkka Soininen9, Iwona Kłoszewska10, Patrizia Mecocci11, Magda Tsolaki12, Bruno Vellas13, Jonathan R Swann4, Abdul Hye13, Simon Lovestone14,15, Cristina Legido-Quigley7,16, Elaine Holmes17,18,19,20. 1. UK Dementia Research Institute, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK. 2. Health Futures Institute, Murdoch University, Perth, WA, 6105, Australia. 3. The Perron Institute for Neurological and Translational Science, Nedlands, WA, 6009, Australia. 4. Section of Bioanalytical Chemistry W12 0NN, UK, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK. 5. National Phenome Centre, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK. 6. imec, Exascience Life Lab, Kapeldreef 75, B-3001, Leuven, Belgium. 7. Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. 8. Present address: Core Metabolomics and Lipidomics Laboratory, Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK. 9. Department of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland. 10. Medical University of Lodz, Lodz, Poland. 11. Institute of Gerontology and Geriatrics, University of Perugia, Perugia, Italy. 12. 3rd Department of Neurology, Aristotle University, Thessaloniki, Greece. 13. INSERM U 558, University of Toulouse, Toulouse, France. 14. Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK. 15. Current affiliation at Janssen-Cilag Ltd, High Wycombe, UK. 16. Steno Diabetes Center Copenhagen, Gentofte, Denmark. 17. UK Dementia Research Institute, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK. elaine.holmes@imperial.ac.uk. 18. Health Futures Institute, Murdoch University, Perth, WA, 6105, Australia. elaine.holmes@imperial.ac.uk. 19. The Perron Institute for Neurological and Translational Science, Nedlands, WA, 6009, Australia. elaine.holmes@imperial.ac.uk. 20. Section for Nutrition Research, Imperial College, Hammersmith Campus Du Cane Road, London, W12 0NN, UK. elaine.holmes@imperial.ac.uk.
Abstract
BACKGROUND: Both serotonergic signalling disruption and systemic inflammation have been associated with the pathogenesis of Alzheimer's disease (AD). The common denominator linking the two is the catabolism of the essential amino acid, tryptophan. Metabolism via tryptophan hydroxylase results in serotonin synthesis, whilst metabolism via indoleamine 2,3-dioxygenase (IDO) results in kynurenine and its downstream derivatives. IDO is reported to be activated in times of host systemic inflammation and therefore is thought to influence both pathways. To investigate metabolic alterations in AD, a large-scale metabolic phenotyping study was conducted on both urine and serum samples collected from a multi-centre clinical cohort, consisting of individuals clinically diagnosed with AD, mild cognitive impairment (MCI) and age-matched controls. METHODS: Metabolic phenotyping was applied to both urine (n = 560) and serum (n = 354) from the European-wide AddNeuroMed/Dementia Case Register (DCR) biobank repositories. Metabolite data were subsequently interrogated for inter-group differences; influence of gender and age; comparisons between two subgroups of MCI - versus those who remained cognitively stable at follow-up visits (sMCI); and those who underwent further cognitive decline (cMCI); and the impact of selective serotonin reuptake inhibitor (SSRI) medication on metabolite concentrations. RESULTS: Results revealed significantly lower metabolite concentrations of tryptophan pathway metabolites in the AD group: serotonin (urine, serum), 5-hydroxyindoleacetic acid (urine), kynurenine (serum), kynurenic acid (urine), tryptophan (urine, serum), xanthurenic acid (urine, serum), and kynurenine/tryptophan ratio (urine). For each listed metabolite, a decreasing trend in concentrations was observed in-line with clinical diagnosis: control > MCI > AD. There were no significant differences in the two MCI subgroups whilst SSRI medication status influenced observations in serum, but not urine. CONCLUSIONS: Urine and serum serotonin concentrations were found to be significantly lower in AD compared with controls, suggesting the bioavailability of the neurotransmitter may be altered in the disease. A significant increase in the kynurenine/tryptophan ratio suggests that this may be a result of a shift to the kynurenine metabolic route due to increased IDO activity, potentially as a result of systemic inflammation. Modulation of the pathways could help improve serotonin bioavailability and signalling in AD patients.
BACKGROUND: Both serotonergic signalling disruption and systemic inflammation have been associated with the pathogenesis of Alzheimer's disease (AD). The common denominator linking the two is the catabolism of the essential amino acid, tryptophan. Metabolism via tryptophan hydroxylase results in serotonin synthesis, whilst metabolism via indoleamine 2,3-dioxygenase (IDO) results in kynurenine and its downstream derivatives. IDO is reported to be activated in times of host systemic inflammation and therefore is thought to influence both pathways. To investigate metabolic alterations in AD, a large-scale metabolic phenotyping study was conducted on both urine and serum samples collected from a multi-centre clinical cohort, consisting of individuals clinically diagnosed with AD, mild cognitive impairment (MCI) and age-matched controls. METHODS: Metabolic phenotyping was applied to both urine (n = 560) and serum (n = 354) from the European-wide AddNeuroMed/Dementia Case Register (DCR) biobank repositories. Metabolite data were subsequently interrogated for inter-group differences; influence of gender and age; comparisons between two subgroups of MCI - versus those who remained cognitively stable at follow-up visits (sMCI); and those who underwent further cognitive decline (cMCI); and the impact of selective serotonin reuptake inhibitor (SSRI) medication on metabolite concentrations. RESULTS: Results revealed significantly lower metabolite concentrations of tryptophan pathway metabolites in the AD group: serotonin (urine, serum), 5-hydroxyindoleacetic acid (urine), kynurenine (serum), kynurenic acid (urine), tryptophan (urine, serum), xanthurenic acid (urine, serum), and kynurenine/tryptophan ratio (urine). For each listed metabolite, a decreasing trend in concentrations was observed in-line with clinical diagnosis: control > MCI > AD. There were no significant differences in the two MCI subgroups whilst SSRI medication status influenced observations in serum, but not urine. CONCLUSIONS: Urine and serum serotonin concentrations were found to be significantly lower in AD compared with controls, suggesting the bioavailability of the neurotransmitter may be altered in the disease. A significant increase in the kynurenine/tryptophan ratio suggests that this may be a result of a shift to the kynurenine metabolic route due to increased IDO activity, potentially as a result of systemic inflammation. Modulation of the pathways could help improve serotonin bioavailability and signalling in ADpatients.
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