Circulating Metabolites Differentiate Acute Ischemic Stroke from Stroke Mimics

Abstract

Objective: Early discrimination of patients with ischemic stroke (IS) from stroke mimics (SMs) poses a diagnostic challenge. The circulating metabolome might reflect pathophysiological events related to acute IS. Here, we investigated the utility of early metabolic changes for differentiating IS from SM. Methods: We performed untargeted metabolomics on serum samples obtained from patients with IS (N = 508) and SM (N = 349; defined by absence of a diffusion weighted imaging [DWI] positive lesion on magnetic resonance imaging [MRI]) who presented to the hospital within 24 hours after symptom onset (median time from symptom onset to blood sampling = 3.3 hours; interquartile range [IQR] = 1.6-6.7 hours) and from neurologically normal controls (NCs; N = 112). We compared diagnostic groups in a discovery-validation approach by applying multivariable linear regression models, machine learning techniques, and propensity score matching. We further performed a targeted look-up of published metabolite sets. Results: Levels of 41 metabolites were significantly associated with IS compared to NCs. The top metabolites showing the highest value in separating IS from SMs were asymmetrical and symmetrical dimethylarginine, pregnenolone sulfate, and adenosine. Together, these 4 metabolites differentiated patients with IS from SMs with an area under the curve (AUC) of 0.90 in the replication sample, which was superior to multimodal cranial computed tomography (CT; AUC = 0.80) obtained for routine diagnostics. They were further superior to previously published metabolite sets detected in our samples. All 4 metabolites returned to control levels by day 90. Interpretation: A set of 4 metabolites with known biological effects relevant to stroke pathophysiology shows unprecedented utility to identify patients with IS upon hospital arrival, thus encouraging further investigation, including multicenter studies.

Metabolomic Profiles of Men and Women Ischemic Stroke Patients

“…The results reveal promising blood-based biomarkers and novel etiologic pathways of ischemic stroke, but the study did not focus on differences in metabolites between men and women AIS patients. While findings from existing studies [13,[26][27][28][29][30][31][32][33][34] highlight the potential of metabolomics for discovering novel circulating biomarkers for stroke and its subtypes, most of the studies did not report gender-differentiated results. Therefore, the specific metabolites and related pathways that are directly associated with men and women AIS patients are not fully understood.…”

“…Knowledge of the underlying metabolic differences might lead to concrete starting points for a future research to improve care for men and women AIS patients. Existing studies [13,14,[26][27][28][29][30][31][32][33][34] that investigated metabolites in stroke focused on differences between stroke and control, hemorrhagic strokes compared with non-hemorrhagic or ischemic strokes. For example, elevated plasma DNA concentrations were detected in patients with hemorrhagic strokes compared with non-hemorrhagic strokes, with a 31% sensitivity and 83% specificity for discriminating the two types of stroke [34].…”

Blood-Based Biomarkers: A Forgotten Friend of Hyperacute Ischemic Stroke

“…Adenosine acts as a vasodilator, inhibits inflammation, and might be neuroprotective ( 48 ). Within 3.3 h after symptom onset, serum adenosine showed a high value in separating IS from SM ( 49 ). In conclusion, RBP4 is a promising biomarker for distinguishing IS from HS patients during the hyperacute phase; and HBD-2 is a potential biomarker in assess prognosis of hyperacute IS.…”

“…Meanwhile, the serum concentration of l -arginine and ADMA/SDMA ratio were correlated with thrombo-inflammation within 6 h after IS onset ( 58 ); these correlations were in turn independently associated with risk of post-stroke infection but not other outcomes ( 58 ). Additionally, within 3.3 h after symptom onset, serum ADMA and SDMA showed a high value in separating IS from SM ( 49 ).…”

“…Pregnenolone sulfate is one of the circulating metabolites. Within 3.3 h after symptom onset, serum pregnenolone sulfate had a high value in differentiating IS from SM ( 49 ).…”