Laure Allard¹, Natacha Turck¹, Pierre R. Burkhard², Nadia Walter^1,3, Anna Rosell⁴, Marianne Gex-Fabry⁵, Denis F. Hochstrasser^1,3,6, Joan Montaner⁴ and Jean-Charles Sanchez¹

¹Biomedical Proteomics Research Group, Department of Structural Biology and Bioinformatics, Medical University Center, CH-1211 Geneva 4, Switzerland. ²Neurology Department, Geneva University Hospital, CH-1211 Geneva 14, Switzerland. ³Biomedical Proteomics Research Group, Central Clinical Chemistry Laboratory, Geneva University Hospital, CH-1211 Geneva 14, Switzerland. ⁴Neurovascular Research Laboratory, Stroke Unit, Vall d’Hebron Hospital, Barcelona, Spain. ⁵Clinical Research Unit, Department of Psychiatry, CH-1225 Chêne-Bourg, Switzerland. ⁶Pharmacy Section, Faculty of Sciences, Geneva University.

Abstract

Background: Efficacy of thrombolysis in acute ischemic stroke is strongly related to physician’s ability to make an accurate diagnosis and to intervene within 3–6 h after event onset. In this context, the discovery and validation of very early blood markers have recently become an urgent, yet unmet, goal of stroke research. Ubiquitin fusion degradation protein 1 is increased in human postmortem CSF, a model of global brain insult, suggesting that its measurement in blood may prove useful as a biomarker of stroke.

Methods: Enzyme-linked immunosorbent assay (ELISA) was used to measure UFD1 in plasma and sera in three independent cohorts, European (Swiss and Spanish) and North-American retrospective analysis encompassing a total of 123 consecutive stroke and 90 control subjects.

Results: Highly significant increase of ubiquitin fusion degradation protein 1 (UFD1) was found in Swiss stroke patients with 71% sensitivity (95% CI, 52–85.8%), and 90% specificity (95% CI, 74.2–98%) (N = 31, p < 0.0001). Significantly elevated concentration of this marker was then validated in Spanish (N = 39, p < 0.0001, 95% sensitivity (95% CI, 82.7–99.4%)), 76% specificity (95% CI, 56.5–89.7%)) and North-American stroke patients (N = 53, 62% sensitivity (95% CI, 47.9–75.2%), 90% specificity (95% CI, 73.5–97.9%), p < 0.0001). Its concentration was increased within 3 h of stroke onset, on both the Swiss (p < 0.0001) and Spanish (p = 0.0004) cohorts.

Conclusions: UFD1 emerges as a reliable plasma biomarker for the early diagnosis of stroke, and in the future, might be used in conjunction with clinical assessments, neuroimaging and other blood markers.

Abbreviations: AUC: area under curve; BBB: blood–brain barrier; CO: cut-off; CSF: cerebrospinal fluid; CT: computerized tomography; H-FABP: heart-fatty acid binding protein; MMP9: matrix metalloproteinase 9; MRI: magnetic resonance imaging; NDKA: nucleotide diphosphate kinase A; OR: odds ratio; RFU: relative fluorescence units; ROC: receiver operating characteristic; rtPA: recombinant tissue plasminogen activator; SE: sensitivity; SP: specificity; TIA: transient ischemic attack; UFD1: ubiquitin fusion degradation protein 1

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