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Targeted Metabolomic Biomarkers for Stroke Subtyping

Translational Stroke Research Aims and scope Submit manuscript

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Abstract

Background and Purpose

Ischemic stroke is a heterogeneous disease with various etiologies. The current subtyping process is complicated, time-consuming, and costly. Metabolite-based biomarkers have the potential to improve classification and deliver optimal treatments. We here aimed to identify novel, targeted metabolomics-based biomarkers to discriminate between large-artery atherosclerosis (LAA) and cardioembolic (CE) stroke.

Methods

We acquired serum samples and clinical data from a hospital-based acute stroke registry (ischemic stroke within 3 days from symptom onset). We included 346 participants (169 LAA, 147 CE, and 30 healthy older adults) and divided them into training and test sets. Targeted metabolomic analysis was performed using quantitative and quality-controlled liquid chromatography with tandem mass spectrometry. A multivariate regression model using metabolomic signatures was created that could independently distinguish between LAA and CE strokes.

Results

The training set (n = 193) identified metabolomic signatures that were different in patients with LAA and CE strokes. Six metabolomic biomarkers, i.e., lysine, serine, threonine, kynurenine, putrescine, and lysophosphatidylcholine acyl C16:0, could discriminate between LAA and CE stroke after adjusting for sex, age, body mass index, stroke severity, and comorbidities. The enhanced diagnostic power of key metabolite combinations for discriminating between LAA and CE stroke was validated using the test set (n = 123).

Conclusions

We observed significant differences in metabolite profiles in LAA and CE strokes. Targeted metabolomics may provide enhanced diagnostic yield for stroke subtypes. The pathophysiological pathways of the identified metabolites should be explored in future studies.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

LAA:

Large-artery atherosclerosis

CE:

Cardioembolic

TOAST:

The Trial of ORG 10172 in Acute Stroke Treatment

rtPA:

Recombinant tissue plasminogen activator

MT:

Mechanical thrombectomy

LC-MS/MS:

Liquid chromatography with tandem mass spectrometry

FDR:

False discovery rate

AUC:

Area under the receiver operating curve

OR:

Odds ratio

CI:

Confidence interval

IDO-1:

Indoleamine 2, 3-dioxygenase 1

KYN/TRP:

Kynurenine/tryptophan ratio

LPC:

Lysophosphatidylcholine

aOR:

Adjusted odds ratio

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Acknowledgements

The bio-specimens and data used for this study were provided by the Biobanks of Seoul National University Hospital and Ajou University Hospital, members of the Korea Biobank Network.

Funding

This work was supported by grants from the National Research Foundation of Korea (NRF), funded by the Korean government (MSIT) (2020R1A2C1100337). The funding agencies had no role in the design of the study.

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Author notes

  1. Eung-Joon Lee and Da Jung Kim contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea

    Eung-Joon Lee, Dong-Wan Kang, Wookjin Yang, Han-Yeong Jeong, Jeong-Min Kim, Sang-Bae Ko, Seung-Hoon Lee & Keun-Hwa Jung

  2. Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea

    Da Jung Kim & Joo-Youn Cho

  3. Metabolomics Core Facility, Department of Transdisciplinary Research and Collaboration, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea

    Da Jung Kim

  4. Department of Neurology, Uijeongbu Eulji Medical Center, Uijeongbu-si, Republic of Korea

    Byung-Woo Yoon

  5. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea

    Joo-Youn Cho

  6. Program in Neuroscience, Seoul National University College of Medicine, Seoul, Republic of Korea

    Keun-Hwa Jung

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  1. Eung-Joon Lee
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Correspondence to Joo-Youn Cho or Keun-Hwa Jung.

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This study was approved by the local institutional review board (Seoul National University Hospital IRB No. 2006-077-1131) and was conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent for blood and clinical data collection was obtained from all the participants.

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Lee, EJ., Kim, D.J., Kang, DW. et al. Targeted Metabolomic Biomarkers for Stroke Subtyping. Transl. Stroke Res. (2023). https://doi.org/10.1007/s12975-023-01137-5

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