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Research paper
New biomarker for acute ischaemic stroke: plasma glycogen phosphorylase isoenzyme BB
  1. Kwang-Yeol Park1,2,
  2. Ilknur Ay1,
  3. Ross Avery1,
  4. Juan Alfredo Caceres3,
  5. Matthew S Siket3,4,
  6. Octavio M Pontes-Neto3,5,
  7. Hui Zheng6,
  8. Natalia S Rost3,
  9. Karen L Furie3,7,
  10. Alma Gregory Sorensen1,
  11. Walter J Koroshetz8,
  12. Hakan Ay1,3
  1. 1AA Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
  2. 2Department of Neurology, Chung-Ang University College of Medicine, Seoul, South Korea
  3. 3Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
  4. 4Division of Emergency Neurosciences, Department of Emergency Medicine, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
  5. 5Stroke Service, Neurology Division, Department of Neuroscience and Behavioral Sciences, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil
  6. 6Biostatistics Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
  7. 7Department of Neurology, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
  8. 8Department of Neurology, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA
  1. Correspondence to Dr Hakan Ay, AA Martinos Center for Biomedical Imaging and Stroke Service, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; hay{at}partners.org

Abstract

Background Glycogen phosphorylase is the key enzyme that breaks down glycogen to yield glucose-1-phosphate in order to restore depleted energy stores during cerebral ischaemia. We sought to determine whether plasma levels of glycogen phosphorylase BB (GPBB) isoform increased in patients with acute ischaemic stroke (AIS).

Methods We studied plasma GPBB levels within 12 hours and again at 48±24 hours of symptom onset in 172 patients with imaging-confirmed AIS and 133 stroke-free individuals. We determined the ability of plasma GPBB to discriminate between cases and controls and examined the predictive value of plasma GPBB for 90-day functional outcome, 90-day survival and acute lesion volumes on neuroimaging.

Results The mean (SD) GPBB levels were higher in cases (46.3±38.6 ng/mL at first measurement and 38.6±36.5 ng/mL at second measurement) than in controls (4.1±7.6 ng/mL, p<0.01 for both). The area under the receiver operating characteristic (ROC) curve for case–control discrimination based on first GPBB measurement was 0.96 (95% CI 0.93 to 0.98). The sensitivity and specificity based on optimal operating point on the ROC curve (7.0 ng/mL) were both 93%. GPBB levels increased in 90% of patients with punctate infarcts (<1.5 mL) and in all patients admitted within the first 4.5 hours of onset. There was no correlation between GPBB concentration and either clinical outcome or acute infarct volume.

Conclusion GPBB demonstrates robust response to acute ischaemia and high sensitivity for small infarcts. If confirmed in more diverse populations that also include stroke mimics, GPBB could find utility as a stand-alone marker for acute brain ischaemia.

  • cerebrovascular disease/stroke
  • infarction
  • embolism
  • biomarker
  • plasma

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Footnotes

  • Contributors HA conceived and designed the study. RA, JAC and OMPN identified the study population and located the plasma samples. HA, RA and KYP acquired clinical, laboratory and imaging data. RA and IA run the GPBB assay. RA performed outcome assessments. HA, IA, KYP and HZ performed statistical analysis. HA, IA, NSR, MSS, KLF, AGS and WJK contributed to the interpretation of results. HA drafted the manuscript. All authors provided critical revision to the manuscript.

  • Competing interests KYP was supported by the Basic Science Research Program through the National Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0023596). IA was supported by NIH grants 1OT2OD023867 and HHSN268201400044C and received research support from Electrocore. OMPN was funded by CNPq grants 402388/2013-5 and 467322/2014-7 and received speaker fees from Boehringer-Ingelheim and Medtronic. NSR received personal compensation for activities with Genzyme, Omniox, Broadview Ventures and CardioNet as a consultant, and Merck for serving on the clinical events committee. NSR received personal compensation in an editorial capacity for Current Treatment Options in Cardiovascular Disease and as a section contributor for UpToDate. NSR is funded by NINDS R01NS086905 and R01NS082285. KLF is a contributing author of UpToDate, Vice Editor of Stroke, Deputy Editor of JNNP, Pfizer DSMB, NINDS research grant P50 NS051343. AGS was an employee of Siemens until January 2016, serves on the board of IMRIS, and has acted as a consultant for Konica Minolta, Permira, EQT Partners, GLG, Third Bridge and Guidepoint in 2016 and 2017. HA received personal compensation as a contributing author of UpToDate.

  • Patient consent Obtained.

  • Ethics approval Partners Institutional Review Board.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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