Circulating metabolites differentiate acute ischemic stroke from stroke mimics

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Objective

Early discrimination of patients with ischemic stroke (IS) from stroke mimics (SM) 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 DWI positive lesion on MRI) who presented to hospital within 24 hours after symptom onset (median time from symptom onset to blood sampling= 3.3h; IQR: 1.6‐6.7h) and from neurologically normal controls (NC, 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 forty‐one metabolites were significantly associated with IS compared to NC. The top metabolites showing the highest value in separating IS from SM were asymmetrical and symmetrical dimethylarginine, pregnenolone sulfate, and adenosine. Together, these four metabolites differentiated patients with IS from SM with an AUC of 0.90 in the replication sample, which was superior to multimodal cranial computed tomography (AUC=0.80) obtained for routine diagnostics. They were further superior to previously published metabolite sets detected in our samples. All four metabolites returned to control levels by day 90.

Interpretation

A set of four 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.

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