Cerebrospinal Fluid Pterins, Pterin-Dependent Neurotransmitters, and Mortality in Pediatric Cerebral Malaria

Matthew P. Rubach; Jackson P. Mukemba; Salvatore M. Florence; Bert K. Lopansri; Keith Hyland; Ryan A. Simmons; Charles Langelier; Sara Nakielny; Joseph L. Derisi; Tsin W. Yeo; Nicholas M. Anstey; J. Brice Weinberg; Esther D. Mwaikambo; Donald L. Granger

doi:10.1093/infdis/jiab086

Cerebrospinal Fluid Pterins, Pterin-Dependent Neurotransmitters, and Mortality in Pediatric Cerebral Malaria

Matthew P. Rubach, Jackson P. Mukemba, Salvatore M. Florence, Bert K. Lopansri, Keith Hyland, Ryan A. Simmons, Charles Langelier, Sara Nakielny, Joseph L. Derisi, Tsin W. Yeo, Nicholas M. Anstey, J. Brice Weinberg, Esther D. Mwaikambo, Donald L. Granger

Research output: Contribution to journal › Article › peer-review

Abstract

Background: Cerebral malaria (CM) pathogenesis remains incompletely understood. Having shown low systemic levels of tetrahydrobiopterin (BH4), an enzymatic cofactor for neurotransmitter synthesis, we hypothesized that BH4 and BH4-dependent neurotransmitters would likewise be low in cerebrospinal fluid (CSF) in CM.

Methods: We prospectively enrolled Tanzanian children with CM and children with nonmalaria central nervous system conditions (NMCs). We measured CSF levels of BH4, neopterin, and BH4-dependent neurotransmitter metabolites, 3-O-methyldopa, homovanillic acid, and 5-hydroxyindoleacetate, and we derived age-adjusted z-scores using published reference ranges.

Results: Cerebrospinal fluid BH4 was elevated in CM (n=49) compared with NMC (n=51) (z-score 0.75 vs -0.08; P<.001). Neopterin was increased in CM (z-score 4.05 vs 0.09; P<.001), and a cutoff at the upper limit of normal (60 nmol/L) was 100% sensitive for CM. Neurotransmitter metabolite levels were overall preserved. A higher CSF BH4/BH2 ratio was associated with increased odds of survival (odds ratio, 2.94; 95% confidence interval, 1.03-8.33; P=.043).

Conclusion: Despite low systemic BH4, CSF BH4 was elevated and associated with increased odds of survival in CM. Coma in malaria is not explained by deficiency of BH4-dependent neurotransmitters. Elevated CSF neopterin was 100% sensitive for CM diagnosis and warrants further assessment of its clinical utility for ruling out CM in malaria-endemic areas.

Original language	English
Pages (from-to)	1432-1441
Number of pages	10
Journal	Journal of Infectious Diseases
Volume	224
Issue number	8
DOIs	https://doi.org/10.1093/infdis/jiab086
Publication status	Published - 15 Oct 2021

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10.1093/infdis/jiab086

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Rubach, M. P., Mukemba, J. P., Florence, S. M., Lopansri, B. K., Hyland, K., Simmons, R. A., Langelier, C., Nakielny, S., Derisi, J. L., Yeo, T. W., Anstey, N. M., Weinberg, J. B., Mwaikambo, E. D., & Granger, D. L. (2021). Cerebrospinal Fluid Pterins, Pterin-Dependent Neurotransmitters, and Mortality in Pediatric Cerebral Malaria. Journal of Infectious Diseases, 224(8), 1432-1441. https://doi.org/10.1093/infdis/jiab086

@article{8401cbb65c0c4e66945d7b6c0ae8e4db,

title = "Cerebrospinal Fluid Pterins, Pterin-Dependent Neurotransmitters, and Mortality in Pediatric Cerebral Malaria",

abstract = "Background: Cerebral malaria (CM) pathogenesis remains incompletely understood. Having shown low systemic levels of tetrahydrobiopterin (BH4), an enzymatic cofactor for neurotransmitter synthesis, we hypothesized that BH4 and BH4-dependent neurotransmitters would likewise be low in cerebrospinal fluid (CSF) in CM. Methods: We prospectively enrolled Tanzanian children with CM and children with nonmalaria central nervous system conditions (NMCs). We measured CSF levels of BH4, neopterin, and BH4-dependent neurotransmitter metabolites, 3-O-methyldopa, homovanillic acid, and 5-hydroxyindoleacetate, and we derived age-adjusted z-scores using published reference ranges. Results: Cerebrospinal fluid BH4 was elevated in CM (n=49) compared with NMC (n=51) (z-score 0.75 vs -0.08; P<.001). Neopterin was increased in CM (z-score 4.05 vs 0.09; P<.001), and a cutoff at the upper limit of normal (60 nmol/L) was 100% sensitive for CM. Neurotransmitter metabolite levels were overall preserved. A higher CSF BH4/BH2 ratio was associated with increased odds of survival (odds ratio, 2.94; 95% confidence interval, 1.03-8.33; P=.043). Conclusion: Despite low systemic BH4, CSF BH4 was elevated and associated with increased odds of survival in CM. Coma in malaria is not explained by deficiency of BH4-dependent neurotransmitters. Elevated CSF neopterin was 100% sensitive for CM diagnosis and warrants further assessment of its clinical utility for ruling out CM in malaria-endemic areas. ",

keywords = "cerebral malaria, neopterin, neurotransmitter, P falciparum, tetrahydrobiopterin",

author = "Rubach, {Matthew P.} and Mukemba, {Jackson P.} and Florence, {Salvatore M.} and Lopansri, {Bert K.} and Keith Hyland and Simmons, {Ryan A.} and Charles Langelier and Sara Nakielny and Derisi, {Joseph L.} and Yeo, {Tsin W.} and Anstey, {Nicholas M.} and Weinberg, {J. Brice} and Mwaikambo, {Esther D.} and Granger, {Donald L.}",

note = "Funding Information: This study was funded by the US National Institute of Allergy and Infectious Diseases (Grants R01AI041764, R01AI041764, K23AI116869). Additional financial support for this research was provided by the US National Institutes of Health (to J. B. W. and D. L. G.), the US Veterans Affairs Medical Research Service (to J. B. W. and D. L. G.), and the Australian National Health and Medical Research Council (to N. M. A. and T. W. Y.). Publisher Copyright: {\textcopyright} 2021 The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = oct,

day = "15",

doi = "10.1093/infdis/jiab086",

language = "English",

volume = "224",

pages = "1432--1441",

journal = "Journal of Infectious Diseases",

issn = "0022-1899",

publisher = "Oxford University Press",

number = "8",

}

Rubach, MP, Mukemba, JP, Florence, SM, Lopansri, BK, Hyland, K, Simmons, RA, Langelier, C, Nakielny, S, Derisi, JL, Yeo, TW , Anstey, NM, Weinberg, JB, Mwaikambo, ED & Granger, DL 2021, 'Cerebrospinal Fluid Pterins, Pterin-Dependent Neurotransmitters, and Mortality in Pediatric Cerebral Malaria', Journal of Infectious Diseases, vol. 224, no. 8, pp. 1432-1441. https://doi.org/10.1093/infdis/jiab086

TY - JOUR

T1 - Cerebrospinal Fluid Pterins, Pterin-Dependent Neurotransmitters, and Mortality in Pediatric Cerebral Malaria

AU - Rubach, Matthew P.

AU - Mukemba, Jackson P.

AU - Florence, Salvatore M.

AU - Lopansri, Bert K.

AU - Hyland, Keith

AU - Simmons, Ryan A.

AU - Langelier, Charles

AU - Nakielny, Sara

AU - Derisi, Joseph L.

AU - Yeo, Tsin W.

AU - Anstey, Nicholas M.

AU - Weinberg, J. Brice

AU - Mwaikambo, Esther D.

AU - Granger, Donald L.

N1 - Funding Information: This study was funded by the US National Institute of Allergy and Infectious Diseases (Grants R01AI041764, R01AI041764, K23AI116869). Additional financial support for this research was provided by the US National Institutes of Health (to J. B. W. and D. L. G.), the US Veterans Affairs Medical Research Service (to J. B. W. and D. L. G.), and the Australian National Health and Medical Research Council (to N. M. A. and T. W. Y.). Publisher Copyright: © 2021 The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/10/15

Y1 - 2021/10/15

N2 - Background: Cerebral malaria (CM) pathogenesis remains incompletely understood. Having shown low systemic levels of tetrahydrobiopterin (BH4), an enzymatic cofactor for neurotransmitter synthesis, we hypothesized that BH4 and BH4-dependent neurotransmitters would likewise be low in cerebrospinal fluid (CSF) in CM. Methods: We prospectively enrolled Tanzanian children with CM and children with nonmalaria central nervous system conditions (NMCs). We measured CSF levels of BH4, neopterin, and BH4-dependent neurotransmitter metabolites, 3-O-methyldopa, homovanillic acid, and 5-hydroxyindoleacetate, and we derived age-adjusted z-scores using published reference ranges. Results: Cerebrospinal fluid BH4 was elevated in CM (n=49) compared with NMC (n=51) (z-score 0.75 vs -0.08; P<.001). Neopterin was increased in CM (z-score 4.05 vs 0.09; P<.001), and a cutoff at the upper limit of normal (60 nmol/L) was 100% sensitive for CM. Neurotransmitter metabolite levels were overall preserved. A higher CSF BH4/BH2 ratio was associated with increased odds of survival (odds ratio, 2.94; 95% confidence interval, 1.03-8.33; P=.043). Conclusion: Despite low systemic BH4, CSF BH4 was elevated and associated with increased odds of survival in CM. Coma in malaria is not explained by deficiency of BH4-dependent neurotransmitters. Elevated CSF neopterin was 100% sensitive for CM diagnosis and warrants further assessment of its clinical utility for ruling out CM in malaria-endemic areas.

AB - Background: Cerebral malaria (CM) pathogenesis remains incompletely understood. Having shown low systemic levels of tetrahydrobiopterin (BH4), an enzymatic cofactor for neurotransmitter synthesis, we hypothesized that BH4 and BH4-dependent neurotransmitters would likewise be low in cerebrospinal fluid (CSF) in CM. Methods: We prospectively enrolled Tanzanian children with CM and children with nonmalaria central nervous system conditions (NMCs). We measured CSF levels of BH4, neopterin, and BH4-dependent neurotransmitter metabolites, 3-O-methyldopa, homovanillic acid, and 5-hydroxyindoleacetate, and we derived age-adjusted z-scores using published reference ranges. Results: Cerebrospinal fluid BH4 was elevated in CM (n=49) compared with NMC (n=51) (z-score 0.75 vs -0.08; P<.001). Neopterin was increased in CM (z-score 4.05 vs 0.09; P<.001), and a cutoff at the upper limit of normal (60 nmol/L) was 100% sensitive for CM. Neurotransmitter metabolite levels were overall preserved. A higher CSF BH4/BH2 ratio was associated with increased odds of survival (odds ratio, 2.94; 95% confidence interval, 1.03-8.33; P=.043). Conclusion: Despite low systemic BH4, CSF BH4 was elevated and associated with increased odds of survival in CM. Coma in malaria is not explained by deficiency of BH4-dependent neurotransmitters. Elevated CSF neopterin was 100% sensitive for CM diagnosis and warrants further assessment of its clinical utility for ruling out CM in malaria-endemic areas.

KW - cerebral malaria

KW - neopterin

KW - neurotransmitter

KW - P falciparum

KW - tetrahydrobiopterin

UR - http://www.scopus.com/inward/record.url?scp=85119480284&partnerID=8YFLogxK

U2 - 10.1093/infdis/jiab086

DO - 10.1093/infdis/jiab086

M3 - Article

C2 - 33617646

AN - SCOPUS:85119480284

SN - 0022-1899

VL - 224

SP - 1432

EP - 1441

JO - Journal of Infectious Diseases

JF - Journal of Infectious Diseases

IS - 8

ER -

Cerebrospinal Fluid Pterins, Pterin-Dependent Neurotransmitters, and Mortality in Pediatric Cerebral Malaria

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