The neuroprotectant nerinetide has shown promise in reducing infarct volumes in primate models of ischemia reperfusion. We hypothesized that early secondary infarct growth after endovascular therapy ...(EVT) (1) may be a suitable surrogate biomarker for testing neuroprotective compounds, (2) is feasible to assess in the acute setting using sequential MRI, and (3) can be modified by treatment with nerinetide.
REPERFUSE-NA1 was a prospective, multisite MRI substudy of the randomized controlled trial ESCAPE-NA1 (ClinicalTrials.gov NCT02930018) that involved patients with acute disabling large vessel occlusive stroke undergoing EVT within 12 hours of onset who were randomized to receive intravenous nerinetide or placebo. Patients enrolled in REPERFUSE-NA1 underwent sequential MRI <5 hours post-EVT (day 1) and at 24 hours (day 2). The primary outcome was total diffusion-weighted MRI infarct growth early after EVT, defined as the lesion volume difference between day 2 and day 1. The secondary outcome was region-specific infarct growth in different brain tissue compartments. Statistical analyses were performed using the Mann-Whitney
test and multiple linear regression.
Sixty-seven of 71 patients included had MRI of sufficient quality. The median infarct volume post-EVT was 12.98 mL (IQR, 5.93-28.08) in the nerinetide group and 10.80 mL (IQR, 3.11-24.45) in the control group (
= 0.59). Patients receiving nerinetide showed a median early secondary infarct growth of 5.92 mL (IQR, 1.09-21.30) compared with 10.80 mL (interquartile range IQR, 2.54-21.81) in patients with placebo (
= 0.30). Intravenous alteplase modified the effect of nerinetide on region-specific infarct growth in white matter and basal ganglia compartments. In patients with no alteplase, the infarct growth rate was reduced by 120% (standard error SE, 60%) in the white matter (
= 0.03) and by 340% (SE, 140%) in the basal ganglia (
= 0.02) in the nerinetide group compared with placebo after adjusting for confounders.
This study highlights the potential of using MR imaging as a biomarker to estimate the effect of a neuroprotective agent in acute stroke treatment. Patients with acute large vessel occlusive stroke exhibited appreciable early infarct growth both in the gray matter and the white matter after undergoing EVT. Acknowledging relatively small overall infarct volumes in this study, treatment with nerinetide was associated with slightly reduced percentage infarct growth in the white matter and basal ganglia compared with placebo in patients not receiving intravenous alteplase and had no effect on the total early secondary infarct growth.
ClinicalTrials.gov NCT02930018.
This study provides Class II evidence that for patients with acute large vessel ischemic stroke undergoing EVT, nerinetide did not significantly decrease early post-EVT infarct growth compared with placebo.
BOLD sensitivity to baseline perfusion and blood volume is a well-acknowledged fMRI confound. Vascular correction techniques based on cerebrovascular reactivity (CVR) might reduce variance due to ...baseline cerebral blood volume, however this is predicated on an invariant linear relationship between CVR and BOLD signal magnitude. Cognitive paradigms have relatively low signal, high variance and involve spatially heterogenous cortical regions; it is therefore unclear whether the BOLD response magnitude to complex paradigms can be predicted by CVR. The feasibility of predicting BOLD signal magnitude from CVR was explored in the present work across two experiments using different CVR approaches. The first utilized a large database containing breath-hold BOLD responses and 3 different cognitive tasks. The second experiment, in an independent sample, calculated CVR using the delivery of a fixed concentration of carbon dioxide and a different cognitive task. An atlas-based regression approach was implemented for both experiments to evaluate the shared variance between task-invoked BOLD responses and CVR across the cerebral cortex. Both experiments found significant relationships between CVR and task-based BOLD magnitude, with activation in the right cuneus (
= 0.64) and paracentral gyrus (
= 0.71), and the left pars opercularis (
= 0.67), superior frontal gyrus (
= 0.62) and inferior parietal cortex (
= 0.63) strongly predicted by CVR. The parietal regions bilaterally were highly consistent, with linear regressions significant in these regions for all four tasks. Group analyses showed that CVR correction increased BOLD sensitivity. Overall, this work suggests that BOLD signal response magnitudes to cognitive tasks are predicted by CVR across different regions of the cerebral cortex, providing support for the use of correction based on baseline vascular physiology.
Abstract only
Background:
Early infarct growth after endovascular therapy (EVT) may lead to unfavorable outcomes despite successful reperfusion. The REPERFUSE-NA1 study replicated the preclinical NA1 ...experiment by investigating the effect of NA1 on early DWI infarct growth in acute ischemic stroke patients receiving EVT.
Methods:
REPERFUSE-NA1 was a sub-study of the randomized controlled trial ESCAPE-NA1 (ClinicalTrialGov NCT02930018). Patients received MRI within 5 hours and 24 hours of EVT. The primary outcome was early diffusion weighted (DWI) infarct growth. The secondary outcome was region-specific DWI infarct growth in the white matter, cortical grey matter and basal ganglia.
Results:
A total of 71 patients was included, of whom 67 had sufficient MR imaging at 5h and 24h post-EVT. For patients who received NA1 compared to placebo, the median age (68.8 v 67.5), baseline NIHSS (15.5 v 16), time from symptom onset to reperfusion (161 v 167 minutes) and mTICI 2b-3 (94.4% v 94.3%) were statistically not different. Median DWI volumes post-EVT (5h) were 13.0 mL (IQR, 5.9-28.1) in NA1 and 13.3 mL (IQR, 3.1-27.0) in placebo. At 24h median DWI volumes increased to 22.6 mL (IQR, 11.2-63.4) in the NA1 group and 22.4 mL (IQR, 7.4-52.3) in the placebo group, equating to a 48.4% DWI volume growth in the NA1 group and a 66.0% growth in the placebo group. Median DWI volume growth was 55.1% for NA1 patients who received alteplase compared to 41.3% for NA1 patients who did not receive alteplase (p=0.65). In terms of region-specific infarct volumes, absolute growth was 2.27mL (IQR, 0.70-6.19) in the white matter, 3.93 mL (IQR, 0.18-12.40) in cortical grey matter, and 1.20 mL (IQR, 0.31-2.62) in basal ganglia in the overall cohort. Between the NA1 and the placebo groups, lesion growth in the white matter (1.96 mL v 2.77mL), cortical gray matter (3.93 mL v 4.07 mL) and basal ganglia (1.62 mL v 0.89 mL) did not differ significantly.
Conclusion:
There was substantial infarct growth early after EVT, with the largest absolute growth in cortical grey matter. No significant effect of NA1 on early infarct growth was observed.
BACKGROUND AND OBJECTIVESThe neuroprotectant nerinetide has shown promise in reducing infarct volumes in primate models of ischemia reperfusion. We hypothesized that early secondary infarct growth ...after endovascular therapy (EVT) (1) may be a suitable surrogate biomarker for testing neuroprotective compounds, (2) is feasible to assess in the acute setting using sequential MRI, and (3) can be modified by treatment with nerinetide.METHODSREPERFUSE-NA1 was a prospective, multisite MRI substudy of the randomized controlled trial ESCAPE-NA1 (ClinicalTrials.gov NCT02930018) that involved patients with acute disabling large vessel occlusive stroke undergoing EVT within 12 hours of onset who were randomized to receive intravenous nerinetide or placebo. Patients enrolled in REPERFUSE-NA1 underwent sequential MRI <5 hours post-EVT (day 1) and at 24 hours (day 2). The primary outcome was total diffusion-weighted MRI infarct growth early after EVT, defined as the lesion volume difference between day 2 and day 1. The secondary outcome was region-specific infarct growth in different brain tissue compartments. Statistical analyses were performed using the Mann-Whitney U test and multiple linear regression.RESULTSSixty-seven of 71 patients included had MRI of sufficient quality. The median infarct volume post-EVT was 12.98 mL (IQR, 5.93-28.08) in the nerinetide group and 10.80 mL (IQR, 3.11-24.45) in the control group (p = 0.59). Patients receiving nerinetide showed a median early secondary infarct growth of 5.92 mL (IQR, 1.09-21.30) compared with 10.80 mL (interquartile range IQR, 2.54-21.81) in patients with placebo (p = 0.30). Intravenous alteplase modified the effect of nerinetide on region-specific infarct growth in white matter and basal ganglia compartments. In patients with no alteplase, the infarct growth rate was reduced by 120% (standard error SE, 60%) in the white matter (p = 0.03) and by 340% (SE, 140%) in the basal ganglia (p = 0.02) in the nerinetide group compared with placebo after adjusting for confounders.DISCUSSIONThis study highlights the potential of using MR imaging as a biomarker to estimate the effect of a neuroprotective agent in acute stroke treatment. Patients with acute large vessel occlusive stroke exhibited appreciable early infarct growth both in the gray matter and the white matter after undergoing EVT. Acknowledging relatively small overall infarct volumes in this study, treatment with nerinetide was associated with slightly reduced percentage infarct growth in the white matter and basal ganglia compared with placebo in patients not receiving intravenous alteplase and had no effect on the total early secondary infarct growth.TRIAL REGISTRATION INFORMATIONClinicalTrials.gov NCT02930018.CLASSIFICATION OF EVIDENCEThis study provides Class II evidence that for patients with acute large vessel ischemic stroke undergoing EVT, nerinetide did not significantly decrease early post-EVT infarct growth compared with placebo.
