A Biomarker for TIA?

Megan Brooks 

November 17, 2011

November 17, 2011 — Patients with acute transient ischemic attack (TIA) have different patterns of gene expression in their blood compared with asymptomatic control patients who have vascular risk factors, researchers have found.

These genes are associated with systemic inflammation and coagulation activation, a finding that supports the plausibility of their biological association with TIA, the researchers say.

"Whether these genes represent potential targets for TIA-specific therapies or biomarkers of TIA requires further study," they note.

Xinhua Zhan, MD, PhD, from the MIND Institute, University of California, Davis, in Sacramento, and colleagues report their research in the November 8 issue of Neurology.

2 Gene Expression Profiles

The researchers write that gene expression profiles derived from blood can be used to distinguish patients with ischemic stroke from healthy individuals. "Whether such profiles exist in patients with acute TIA is unknown," they add.

To investigate, Dr. Zhan and colleagues used microarray technology to examine RNA gene expression in 26 patients with acute TIA and 26 control participants who had risk factors for vascular disease, such as hypertension, diabetes, and hyperlipidemia, but who did not have symptomatic cardiovascular disease.

They identified 449 genes that were differentially expressed in the blood of patients with TIA as compared with the control participants. Prediction analysis for TIA revealed a set of 34 genes that optimally distinguished TIA from control participants with 100% sensitivity and specificity.

Additional analysis revealed 2 patterns of gene expression, which divided the overall TIA cohort into 2 groups. "The clinical significance of these RNA subtypes remains unclear," the researchers note.

Dr. Zhan and colleagues said it was noteworthy that 3 patients who had evidence of infarction on magnetic resonance diffusion-weighted imaging, and 1 patient who had a subsequent stroke within 90 days of having a TIA, were clustered together into 1 of these groups.

"[This raises] the possibility that this pattern of gene expression might signify a high-risk group of patients with TIA," Brett Cucchiara, MD, from the University of Pennsylvania School of Medicine, Philadelphia, and Paul Nyquist, MD, MPH, from Johns Hopkins University School of Medicine, Baltimore, Maryland, point out in a linked commentary.

Chronic Inflammatory State?

Functional analysis by Dr. Zhan's team indicates that the genes associated with TIA are also associated with systemic inflammation, platelet activation, and prothrombin activation. The data "strongly suggest that different patterns of immune activation may exist in TIA," they say.

It is unclear at present whether the gene expression patterns existed before the onset of TIA, or whether they were a result of acute TIA.

However, when the researchers compared gene expression in blood drawn within 24 hours of a TIA to gene expression in blood drawn between 24 and 72 hours of an attack, they found that more than 90% of the genes expressed within 24 hours were similar to those expressed between 24 and 72 hours.

"Though further studies of gene expression over time are required, this suggests that there may be a chronic inflammatory state in TIA that contributes to the development of symptomatic cerebrovascular disease," the researchers write.

Some of the TIA-associated genes are involved in primary and secondary hemostasis. The finding that tissue factor pathway inhibitor (an inhibitor of thrombin and factor Xa) was upregulated in patients with TIA is interesting because it suggests that "differential regulation of the coagulation cascade and clot formation may be present in TIA."

Genes encoding collagens and peptidases that break down von Willebrand factor (vWF) were also upregulated in patients with TIA.

"Though peptidases that break down vWF have been associated with stroke and thrombotic thrombocytopenic purpura, this is the first report in TIA," Dr. Zhan and colleagues point out. "These data suggest that procoagulant features are present in TIA that might provide treatment targets," they say.

Reason for Hope?

The small sample size (52 patients) is a limitation of the study, Dr. Zhan and colleagues say, and replication in a separate, larger cohort is needed.

In their editorial, Dr. Cucchiara and Dr. Nyquist note that the case-control design of the study is "particularly problematic given the lack of a clear gold standard for the diagnosis of TIA."

"Another concern is the possibility that factors other than acute cerebral ischemia differed between the TIA and control subjects that could account for the identified variations in gene expression," they write.

Dr. Cucchiara and Dr. Nyquist say the search for useful blood markers for acute cerebrovascular disease has so far been largely unsuccessful. The results of this study "give reason for hope, but also suggest that the path forward will be long, complex, and challenging."

Dr. Zhan told Medscape Medical News that she is confident that "RNA expression in blood will eventually be used as a blood diagnostic test for TIAs."

The next steps, she said, are to "validate the findings in a larger cohort of TIAs; verify the peripheral inflammatory state in TIA patients; and determine if one of the TIA subgroups is at a very high risk for stroke."

The study was supported by the National Institutes of Health and the AHA Bugher Foundation. Dr. Zhan is coholder of a patent regarding the use of blood RNA in TIA. A complete list of author disclosures is listed with the original article. Dr. Cucchiara reports serving on the data safety monitoring board for Wyeth, now part of Pfizer, Inc. He also discloses ties with Boehringer Ingelheim; diaDexus, Inc; UpToDate, Inc; Ferrer; and iNova Pharmaceuticals. Dr. Nyquist has disclosed no relevant financial relationships.

Neurology. 2011;77:1716-1724. Abstract, Editorial

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