Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Malaria Journal
Published in: Malaria Journal 1/2017

Open Access 01-12-2017 | Research

Cerebrospinal fluid kynurenine and kynurenic acid concentrations are associated with coma duration and long-term neurocognitive impairment in Ugandan children with cerebral malaria

Authors: Dag Holmberg, Elisabeth Franzén-Röhl, Richard Idro, Robert O. Opoka, Paul Bangirana, Carl M. Sellgren, Ronny Wickström, Anna Färnert, Lilly Schwieler, Göran Engberg, Chandy C. John

Published in: Malaria Journal | Issue 1/2017

Login to get access

Abstract

Background

One-fourth of children with cerebral malaria (CM) retain cognitive sequelae up to 2 years after acute disease. The kynurenine pathway of the brain, forming neuroactive metabolites, e.g. the NMDA-receptor antagonist kynurenic acid (KYNA), has been implicated in long-term cognitive dysfunction in other CNS infections. In the present study, the association between the kynurenine pathway and neurologic/cognitive complications in children with CM was investigated.

Methods

Cerebrospinal fluid (CSF) concentrations of KYNA and its precursor kynurenine in 69 Ugandan children admitted for CM to Mulago Hospital, Kampala, Uganda, between 2008 and 2013 were assessed. CSF kynurenine and KYNA were compared to CSF cytokine levels, acute and long-term neurologic complications, and long-term cognitive impairments. CSF kynurenine and KYNA from eight Swedish children without neurological or infectious disease admitted to Astrid Lindgren’s Children’s Hospital were quantified and used for comparison.

Results

Children with CM had significantly higher CSF concentration of kynurenine and KYNA than Swedish children (P < 0.0001 for both), and CSF kynurenine and KYNA were positively correlated. In children with CM, CSF kynurenine and KYNA concentrations were associated with coma duration in children of all ages (P = 0.003 and 0.04, respectively), and CSF kynurenine concentrations were associated with worse overall cognition (P = 0.056) and attention (P = 0.003) at 12-month follow-up in children ≥5 years old.

Conclusions

CSF KYNA and kynurenine are elevated in children with CM, indicating an inhibition of glutamatergic and cholinergic signaling. This inhibition may lead acutely to prolonged coma and long-term to impairment of attention and cognition.
Literature
1.
Idro R, Marsh K, John CC, Newton CRJ. Cerebral malaria: mechanisms of brain injury and strategies for improved neurocognitive outcome. Pediatr Res. 2010;68:267–74.CrossRefPubMedPubMedCentral
2.
John CC, Panoskaltsis-Mortari A, Opoka RO, Park GS, Orchard PJ, Jurek AM, et al. Cerebrospinal fluid cytokine levels and cognitive impairment in cerebral malaria. Am J Trop Med Hyg. 2008;78:198–205.PubMedPubMedCentral
3.
John CC, Bangirana P, Byarugaba J, Opoka RO, Idro R, Jurek AM, et al. Cerebral malaria in children is associated with long-term cognitive impairment. Pediatrics. 2008;122:E92–9.CrossRefPubMedPubMedCentral
4.
Boivin MJ, Bangirana P, Byarugaba J, Opoka RO, Idro R, Jurek AM, et al. Cognitive impairment after cerebral malaria in children: a prospective study. Pediatrics. 2007;119:E360–6.CrossRefPubMedPubMedCentral
5.
Boivin MJ. Effects of early cerebral malaria on cognitive ability in Senegalese children. J Dev Behav Pediatr. 2002;23:353–64.CrossRefPubMed
6.
Carter JA, Mung’ala-Odera V, Neville BGR, Murira G, Mturi N, Musumba C, et al. Persistent neurocognitive impairments associated with severe falciparum malaria in Kenyan children. J Neurol Neurosurg Psychiatry. 2005;76:476–81.CrossRefPubMedPubMedCentral
7.
Holding PA, Stevenson J, Peshu N, Marsh K. Cognitive sequelae of severe malaria with impaired consciousness. Trans R Soc Trop Med Hyg. 1999;93:529–34.CrossRefPubMed
8.
Cunnington AJ, Riley EM, Walther M. Stuck in a rut? Reconsidering the role of parasite sequestration in severe malaria syndromes. Trends Parasitol. 2013;29:585–92.CrossRefPubMed
9.
Mackintosh CL, Beeson JG, Marsh K. Clinical features and pathogenesis of severe malaria. Trends Parasitol. 2004;20:597–603.CrossRefPubMed
10.
11.
Alexander KS, Wu HQ, Schwarcz R, Bruno JP. Acute elevations of brain kynurenic acid impair cognitive flexibility: normalization by the alpha7 positive modulator galantamine. Psychopharmacology. 2012;220:627–37.CrossRefPubMed
12.
Ibrahim HM, Tamminga CA. Treating impaired cognition in schizophrenia. Curr Pharm Biotechnol. 2012;13:1587–94.CrossRefPubMed
13.
Labrie V, Lipina T, Roder JC. Mice with reduced NMDA receptor glycine affinity model some of the negative and cognitive symptoms of schizophrenia. Psychopharmacology. 2008;200:217–30.CrossRefPubMed
14.
Atlas A, Gisslen M, Nordin C, Lindstrom L, Schwieler L. Acute psychotic symptoms in HIV-1 infected patients are associated with increased levels of kynurenic acid in cerebrospinal fluid. Brain Behav Immun. 2007;21:86–91.CrossRefPubMed
15.
Atlas A, Franzen-Röhl E, Söderlund J, Jönsson EG, Samuelsson M, Schwieler L, et al. Sustained elevation of kynurenic acid in the cerebrospinal fluid of patients with herpes simplex virus Type 1 encephalitis. Int J Tryptophan Res. 2013;6:89–96.PubMedPubMedCentral
16.
Holtze M, Mickiene A, Atlas A, Lindquist L, Schwieler L. Elevated cerebrospinal fluid kynurenic acid levels in patients with tick-borne encephalitis. J Intern Med. 2012;272:394–401.CrossRefPubMed
17.
Schwieler L, Erhardt S, Nilsson L, Linderholm K, Engberg G. Effects of COX-1 and COX-2 inhibitors on the firing of rat midbrain dopaminergic neurons—possible involvement of endogenous kynurenic acid. Synapse. 2006;59:290–8.CrossRefPubMed
18.
Pocivavsek A, Wu HQ, Potter MC, Elmer GI, Pellicciari R, Schwarcz R. Fluctuations in endogenous kynurenic acid control hippocampal glutamate and memory. Neuropsychopharmacology. 2011;36:2357–67.CrossRefPubMedPubMedCentral
19.
Dobbie M, Crawley J, Waruiru C, Marsh K, Surtees R. Cerebrospinal fluid studies in children with cerebral malaria: an excitotoxic mechanism? Am J Trop Med Hyg. 2000;62:284–90.CrossRefPubMed
20.
Bangirana P, Opoka RO, Boivin MJ, Idro R, Hodges JS, Romero RA, et al. Severe malarial anemia is associated with long-term neurocognitive impairment. Clin Infect Dis. 2014;59:336–44.CrossRefPubMedPubMedCentral
21.
Swartz KJ, Matson WR, Macgarvey U, Ryan EA, Beal MF. Measurement of kynurenic acid in mammalian brain extracts and cerebrospinal fluid by high-performance liquid chromatography with fluorometric and coulometric electrode array detection. Anal Biochem. 1990;185:363–76.CrossRefPubMed
22.
John CC, Moormann AM, Sumba PO, Ofulla AV, Pregibon DC, Kazura JW. Gamma interferon responses to Plasmodium falciparum liver-stage antigen 1 and thrombospondin-related adhesive protein and their relationship to age, transmission intensity, and protection against malaria. Infect Immun. 2004;72:5135–42.CrossRefPubMedPubMedCentral
23.
Mullen EM. Mullen Scales of Early Learning:AGS Edition.1995.
24.
Goldman DZ, Shapiro EG, Nelson CA. Measurement of vigilance in 2-year-old children. Dev Neuropsychol. 2004;25:227–50.CrossRefPubMed
25.
Medana IM, Hien TT, Day NP, Phu NH, Mai NTH, Chu’ong LV, et al. The clinical significance of cerebrospinal fluid levels of kynurenine pathway metabolites and lactate in severe malaria. J Infect Dis. 2002;185:650–6.CrossRefPubMed
26.
Medana IM, Day NPJ, Salahifar-Sabet H, Stocker R, Smythe G, Bwanaisa L, et al. Metabolites of the kynurenine pathway of tryptophan metabolism in the cerebrospinal fluid of Malawian children with malaria. J Infect Dis. 2003;188:844–9.CrossRefPubMed
27.
Hunt NH, Golenser J, Chan-Ling T, Parekh S, Rae C, Potter S, et al. Immunopathogenesis of cerebral malaria. Int J Parasitol. 2006;36:569–82.CrossRefPubMed
28.
Miu J, Ball HJ, Mellor AL, Hunt NH. Effect of indoleamine dioxygenase-1 deficiency and kynurenine pathway inhibition on murine cerebral malaria. Int J Parasitol. 2009;39:363–70.CrossRefPubMed
29.
Hunt NH, Too LK, Khaw LT, Guo J, Hee L, Mitchell AJ, et al. The kynurenine pathway and parasitic infections that affect CNS function. Neuropharmacology. 2017;112:389–98.CrossRefPubMed
30.
Linderholm K, Powell S, Olsson E, Holtze M, Snodgrass R, Erhardt S. Role of the NMDA-receptor in prepulse inhibition in the rat. Int J Tryptophan Res. 2010;3:1–12.CrossRefPubMedPubMedCentral
31.
Erhardt S, Blennow K, Nordin C, Skogh E, Lindstrom LH, Engberg G. Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Neurosci Lett. 2001;313:96–8.CrossRefPubMed
32.
Olsson SK, Samuelsson M, Saetre P, Lindstrom L, Jonsson EG, Nordin C, et al. Elevated levels of kynurenic acid in the cerebrospinal fluid of patients with bipolar disorder. J Psychiatry Neurosci. 2010;35:195–9.CrossRefPubMedPubMedCentral
33.
Kepplinger B, Baran H, Kainz A, Ferraz-Leite H, Newcombe J, Kalina P. Age-related increase of kynurenic acid in human cerebrospinal fluid-IgG and beta(2)-microglobulin changes. Neurosignals. 2005;14:126–35.CrossRefPubMed
34.
Nilsson LK, Nordin C, Jonsson EG, Engberg G, Linderholm KR, Erhardt S. Cerebrospinal fluid kynurenic acid in male and female controls–correlation with monoamine metabolites and influences of confounding factors. J Psychiatr Res. 2007;41:144–51.CrossRefPubMed
35.
Linderholm KR, Skogh E, Olsson SK, Dahl ML, Holtze M, Engberg G, et al. Increased levels of kynurenine and kynurenic acid in the CSF of patients with schizophrenia. Schizophr Bull. 2012;38:426–32.CrossRefPubMed
36.
Guillemin GJ, Smythe G, Takikawa O, Brew BJ. Expression of indoleamine 2,3-dioxygenase and production of quinolinic acid by human microglia, astrocytes, and neurons. Glia. 2005;49:15–23.CrossRefPubMed
37.
Schwieler L, Larsson MK, Skogh E, Kegel ME, Orhan F, Abdelmoaty S, et al. Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia - significance for activation of the kynurenine pathway. J Psychiatry Neurosci. 2015;40:126–33.PubMedPubMedCentral
38.
Medana IM, Hunt NH, Chaudhri G. Tumor necrosis factor-alpha expression in the brain during fatal murine cerebral malaria: evidence for production by microglia and astrocytes. Am J Pathol. 1997;150:1473–86.PubMedPubMedCentral
39.
Mandi Y, Vecsei L. The kynurenine system and immunoregulation. J Neural Transm. 2012;119:197–209.CrossRefPubMed
40.
Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, et al. Subanesthetic effects of the noncompetetive NMDA antagonist, ketamine, in humans: psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994;51:199–214.CrossRefPubMed
41.
Chess AC, Simoni MK, Alling TE, Bucci DJ. Elevations of endogenous kynurenic acid produce spatial working memory deficits. Schizophr Bull. 2007;33:797–804.CrossRefPubMed
42.
Potter MC, Elmer GI, Bergeron R, Albuquerque EX, Guidetti P, Wu HQ, et al. Reduction of endogenous kynurenic acid formation enhances extracellular glutamate, hippocampal plasticity, and cognitive behavior. Neuropsychopharmacology. 2010;35:1734–42.PubMedPubMedCentral
43.
Kozak R, Campbell BM, Strick CA, Horner W, Hoffmann WE, Kiss T, et al. Reduction of brain kynurenic acid improves cognitive function. J Neurosci. 2014;34:10592–602.CrossRefPubMed
44.
Stone TW, Forrest CM, Darlington LG. Kynurenine pathway inhibition as a therapeutic strategy for neuroprotection. FEBS J. 2012;279:1386–97.CrossRefPubMed
45.
Ultanir SK, Kim JE, Hall BJ, Deerinck T, Ellisman M, Ghosh A. Regulation of spine morphology and spine density by NMDA receptor signaling in vivo. Proc Natl Acad Sci USA. 2007;104:19553–8.CrossRefPubMedPubMedCentral
46.
Lohmann C, Kessels HW. The developmental stages of synaptic plasticity. J Physiol. 2014;592:13–31.CrossRefPubMed
47.
Forrest CM, McNair K, Pisar M, Khalil OS, Darlington LG, Stone TW. Altered hippocampal plasticity by prenatal kynurenine administration, kynurenine-3-monogenase (KMO) deletion or galantamine. Neuroscience. 2015;310:91–105.CrossRefPubMedPubMedCentral
Metadata
Title
Cerebrospinal fluid kynurenine and kynurenic acid concentrations are associated with coma duration and long-term neurocognitive impairment in Ugandan children with cerebral malaria
Authors
Dag Holmberg
Elisabeth Franzén-Röhl
Richard Idro
Robert O. Opoka
Paul Bangirana
Carl M. Sellgren
Ronny Wickström
Anna Färnert
Lilly Schwieler
Göran Engberg
Chandy C. John
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Malaria Journal / Issue 1/2017
Electronic ISSN: 1475-2875
DOI
https://doi.org/10.1186/s12936-017-1954-1

Other articles of this Issue 1/2017

Malaria Journal 1/2017 Go to the issue

Research

School-based diagnosis and treatment of malaria by teachers using rapid diagnostic tests and artemisinin-based combination therapy: experiences and perceptions of users and implementers of the Learner Treatment Kit, southern Malawi

Research

Towards a needle-free diagnosis of malaria: in vivo identification and classification of red and white blood cells containing haemozoin

Research

Development of Plasmodium falciparum specific naïve, atypical, memory and plasma B cells during infancy and in adults in an endemic area

Research

Longitudinal estimation of Plasmodium falciparum prevalence in relation to malaria prevention measures in six sub-Saharan African countries

Research

Testing times: trends in availability, price, and market share of malaria diagnostics in the public and private healthcare sector across eight sub-Saharan African countries from 2009 to 2015

Research

The shape of the iceberg: quantification of submicroscopic Plasmodium falciparum and Plasmodium vivax parasitaemia and gametocytaemia in five low endemic settings in Ethiopia
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits