W. Taylor Kimberly, MD, PhD
Taylor Kimberly is a stroke and critical care neurologist in the Department of Neurology. Dr. Kimberly’s research group studies metabolomic and neuroimaging biomarkers of stroke and cerebral edema. The overarching goal is to identify novel biomarkers and candidate therapeutic targets for secondary brain injury. A key focus is to design and conduct multicenter clinical studies targeting brain edema, applying biomarkers to probe pharmacologic mechanisms and guide the development of novel therapeutic agents in stroke.
Questions being addressed in the lab
- Does ABCC8 / sulfonylurea receptor 1 (Sur1) mediate brain edema after large hemispheric infarction in stroke patients?
- How does acute inflammation lead to brain edema and which patients suffer worse outcomes as a result?
- What novel risk predictors can be identified using metabolite profiling for incident stroke?
Projects underway to answer these questions
We are leading an international clinical trial that is testing the Sur1 inhibitor glyburide for the prevention of brain edema after large hemispheric stroke. Following the successful completion of phase 2a and 2b studies, we currently co-lead the CHARM study, a phase 3 randomized, placebo-controlled, double-blind trial testing the clinical efficacy of intravenous glyburide for the prevention of brain edema after large hemispheric stroke (gov Identifier: NCT02864953).
Our group develops and evaluates neuroimaging and proteomic biomarkers that guide prognosis and treatment decisions after acute brain injury. A major focus is to characterize which patients are prone to edema formation and its relationship to subsequent neurological recovery. Having established tools to non-invasively characterize brain edema in patients, we identify novel pathways that are markers for and contribute to brain edema formation. Our analyses suggest that the sterile, innate inflammatory response to ischemia drives edema formation and contributes to worse outcome.
We investigate novel metabolomic predictors of incident stroke in community-based cohorts, using a liquid chromatography-tandem mass spectrometry platform designed for high-throughput metabolite profiling of patient biospecimens. Our group has developed a novel targeted metabolomics method that can detect ~200 polar metabolites in small sample volumes with enhanced sensitivity and reliability. Previously we have applied the technique to predictors of cardiometabolic traits, and have turned our attention to the identification of risk predictors for stroke subtypes.
GAMES-RP Trial (ClinicalTrials.gov Identifier: NCT01794182). We completed a phase 2b study, GAMES-RP, which was a multicenter, randomized, double-blind, placebo-controlled trial testing intravenous glyburide (RP-1127) for the prevention of brain edema. This study showed a reduction in brain edema, as measured by midline shift, and a reduction in the edema biomarker, matrix metalloproteinase-9 (MMP-9). Treatment with intravenous glyburide was also associated with a 50% reduction in mortality and evidence of improved outcome
We have developed several imaging tools to non-invasively quantify brain edema in patients, in order to study which patients are impacted by its development. We have found that brain edema is a significant source of secondary injury in about one quarter of all strokes, corresponding to a substantially larger proportion of patients than previously appreciated. Our analyses suggest that the innate inflammatory response is linked to the formation of edema, and the subsequent risk of death and disability.
We have also developed a novel metabolomics method that can measure >200 metabolites simultaneously in a small biospecimen volume. We have identified several key metabolites associated with outcome, including the endocannabinoid anandamide, which may serve as a prognostic biomarker for secondary brain injury. In other studies, we have identified that impaired oxidative phosphorylation may be linked to atrial fibrillation-associated stroke risk. These studies may help guide secondary stroke risk reduction, particularly in patients who have embolic stroke of undetermined source.
Highlighted Publications from the lab
Safety and efficacy of intravenous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): a randomised, double-blind, placebo-controlled phase 2 trial