Capillary blood protein markers of posttraumatic headache in children after concussion

Feiven Fan Murdoch Children’s Research Institute, Melbourne, Victoria;
Melbourne School of Psychological Sciences, University of Melbourne, Victoria;

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Franz E. Babl Murdoch Children’s Research Institute, Melbourne, Victoria;
Departments of Pediatrics,
Critical Care, and
Emergency Department, Royal Children’s Hospital, Melbourne, Victoria;

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Ella E. K. Swaney Murdoch Children’s Research Institute, Melbourne, Victoria;
Departments of Pediatrics,

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Stephen J. C. Hearps Murdoch Children’s Research Institute, Melbourne, Victoria;
Critical Care, and

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Michael Takagi Murdoch Children’s Research Institute, Melbourne, Victoria;
Melbourne School of Psychological Sciences, University of Melbourne, Victoria;
Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Melbourne, Victoria;

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Samantha J. Emery-Corbin Advanced Technology and Biology Division, Walter and Eliza Hall Institute, Melbourne, Victoria;
Medical Biology, University of Melbourne, Victoria;

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Laura F. Dagley Advanced Technology and Biology Division, Walter and Eliza Hall Institute, Melbourne, Victoria;
Medical Biology, University of Melbourne, Victoria;

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Jumana Yousef Advanced Technology and Biology Division, Walter and Eliza Hall Institute, Melbourne, Victoria;
Medical Biology, University of Melbourne, Victoria;

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Georgia M. Parkin Murdoch Children’s Research Institute, Melbourne, Victoria;

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Vanessa C. Rausa Murdoch Children’s Research Institute, Melbourne, Victoria;
Departments of Pediatrics,

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Nicholas Anderson Murdoch Children’s Research Institute, Melbourne, Victoria;

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Fabian Fabiano Murdoch Children’s Research Institute, Melbourne, Victoria;
Melbourne School of Psychological Sciences, University of Melbourne, Victoria;

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Kevin Dunne Murdoch Children’s Research Institute, Melbourne, Victoria;
Departments of Pediatrics,
Department of Rehabilitation Medicine, Royal Children’s Hospital, Melbourne, Victoria;

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Marc Seal Murdoch Children’s Research Institute, Melbourne, Victoria;
Departments of Pediatrics,

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Gavin A. Davis Murdoch Children’s Research Institute, Melbourne, Victoria;
Department of Neurosurgery, Austin and Cabrini Hospitals, Melbourne, Victoria;

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Chantal Attard Murdoch Children’s Research Institute, Melbourne, Victoria;
Departments of Pediatrics,

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Vicki Anderson Murdoch Children’s Research Institute, Melbourne, Victoria;
Melbourne School of Psychological Sciences, University of Melbourne, Victoria;
Departments of Pediatrics,
Psychology Service, Royal Children’s Hospital, Melbourne, Victoria, Australia;

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Vera Ignjatovic Murdoch Children’s Research Institute, Melbourne, Victoria;
Departments of Pediatrics,
Johns Hopkins All Children’s Institute for Clinical & Translational Research, St. Petersburg, Florida; and
Department of Pediatrics, School of Medicine, Johns Hopkins University, Baltimore, Maryland

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OBJECTIVE

Posttraumatic headache (PTH) represents the most common acute and persistent symptom in children after concussion, yet there is no blood protein signature to stratify the risk of PTH after concussion to facilitate early intervention. This discovery study aimed to identify capillary blood protein markers, at emergency department (ED) presentation within 48 hours of concussion, to predict children at risk of persisting PTH at 2 weeks postinjury.

METHODS

Capillary blood was collected using the Mitra Clamshell device from children aged 8–17 years who presented to the ED of the Royal Children’s Hospital, Melbourne, Australia, within 48 hours of sustaining a concussion. Participants were followed up at 2 weeks postinjury to determine PTH status. PTH was defined per clinical guidelines as a new or worsened headache compared with preinjury. An untargeted proteomics analysis using data-independent acquisition (DIA) was performed. Principal component analysis and hierarchical clustering were used to reduce the dimensionality of the protein dataset.

RESULTS

A total of 907 proteins were reproducibly identified from 82 children within 48 hours of concussion. The mean participant age was 12.78 years (SD 2.54 years, range 8–17 years); 70% of patients were male. Eighty percent met criteria for acute PTH in the ED, while one-third of participants with follow-up experienced PTH at 2 weeks postinjury (range 8–16 days). Hemoglobin subunit zeta (HBZ), cystatin B (CSTB), beta-ala-his dipeptidase (CNDP1), hemoglobin subunit gamma-1 (HBG1), and zyxin (ZYX) were weakly associated with PTH at 2 weeks postinjury based on up to a 7% increase in the PTH group despite nonsignificant Benjamini-Hochberg adjusted p values.

CONCLUSIONS

This discovery study determined that no capillary blood protein markers, measured at ED presentation within 48 hours of concussion, can predict children at risk of persisting PTH at 2 weeks postinjury. While HBZ, CSTB, CNDP1, HBG1, and ZYX were weakly associated with PTH at 2 weeks postinjury, there was no specific blood protein signature predictor of PTH in children after concussion. There is an urgent need to discover new blood biomarkers associated with PTH to facilitate risk stratification and improve clinical management of pediatric concussion.

ABBREVIATIONS

ATOX1 = antioxidant 1 copper chaperone; AUC = area under the curve; CNDP1 = beta-ala-his dipeptidase; CSTB = cystatin B; DIA = data-independent acquisition; ED = emergency department; FC = fold change; FDR = false discovery rate; HBG1 = hemoglobin subunit gamma-1; HBZ = hemoglobin subunit zeta; ICHD-3 = International Classification of Headache Disorders, 3rd Edition; MS = mass spectrometry; mTBI = mild TBI; NT5C3A = cytosolic 5′-nucleotidase 3A; PCA = principal component analysis; PCSI = Post-Concussion Symptom Inventory; PTH = posttraumatic headache; RCH = Royal Children’s Hospital; SPARC = secreted protein acidic and rich in cysteine; TBI = traumatic brain injury; ZYX = zyxin.

Supplementary Materials

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