Comparing mismatch strategies for patients being considered for ischemic stroke tenecteplase trials.

BACKGROUND: Currently there are multiple variations of imaging-based patient selection mismatch methods in ischemic stroke. In the present study, we sought to compare the two most common mismatch methods and identify if there were different effects on the outcome of a randomized clinical trial depending on the mismatch method used. AIMS: Investigate the effect of clinical and imaging-based mismatch criteria on patient outcomes of a pooled cohort from randomized trials of intravenous tenecteplase versus alteplase. METHODS: Baseline clinical and imaging scores were used to categorize patients as meeting either the DAWN mismatch (baseline NIHSS ≥ 10, and age cut-offs for ischemic core volume) or DEFUSE 2 mismatch criteria (mismatch volume > 15 mL, mismatch ratio > 1.8 and ischemic core < 70 mL). We then investigated whether tenecteplase-treated patients had favorable odds of less disability (on modified Rankin scale, mRS) compared to those treated with alteplase, for clinical and imaging mismatch, respectively. RESULTS: From 146 pooled patients, 71 received alteplase and 75 received tenecteplase. The overall pooled group did not show improved patient outcomes when treated with tenecteplase (mRS 0-1 OR 1.77, 95% CI 0.89-3.51, p = 0.102) compared with alteplase. A total of 39 (27%) patients met both clinical and imaging mismatch criteria, 25 (17%) patients met only imaging criteria, 36 (25%) met only clinical mismatch criteria and, finally, 46 (31%) did not meet either of imaging or mismatch criteria. Patients treated with tenecteplase had more favorable outcomes when they met either imaging mismatch (mRS 0-1, OR 2.33, 95% CI 1.13-5.94, p = 0.032) or clinical mismatch criteria (mRS 0-1, OR 2.15, 95% CI 1.142, 8.732, p = 0.027) but with differing proportions. CONCLUSION: Target mismatch selection was more inclusive and exhibited in a larger treatment effect between tenecteplase and alteplase.

Patient-Specific iPSC Model of a Genetic Vascular Dementia Syndrome Reveals Failure of Mural Cells to Stabilize Capillary Structures.

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most common form of genetic stroke and vascular dementia syndrome resulting from mutations in NOTCH3. To elucidate molecular mechanisms of the condition and identify drug targets, we established a patient-specific induced pluripotent stem cell (iPSC) model and demonstrated for the first time a failure of the patient iPSC-derived vascular mural cells (iPSC-MCs) in engaging and stabilizing endothelial capillary structures. The patient iPSC-MCs had reduced platelet-derived growth factor receptor ß, decreased secretion of the angiogenic factor vascular endothelial growth factor (VEGF), were highly susceptible to apoptotic insults, and could induce apoptosis of adjacent endothelial cells. Supplementation of VEGF significantly rescued the capillary destabilization. Small interfering RNA knockdown of NOTCH3 in iPSC-MCs revealed a gain-of-function mechanism for the mutant NOTCH3. These disease mechanisms likely delay brain repair after stroke in CADASIL, contributing to the brain hypoperfusion and dementia in this condition, and will help to identify potential drug targets.

Vasoreactivity in CADASIL: Comparison to structural MRI and neuropsychology.

Impaired cerebrovascular reactivity precedes histological and clinical evidence of CADASIL in animal models. We aimed to more fully characterise peripheral and cerebral vascular function and reactivity in a cohort of adult CADASIL patients, and explore the associations of these with conventional clinical, imaging and neuropsychological measures. A total of 22 adults with CADASIL gave informed consent to participate in an exploratory study of vascular function in CADASIL. Clinical assessment, comprehensive vascular assessment, MRI and neuropsychological testing were conducted. We measured cerebral vasoreactivity with transcranial Doppler and arterial spin labelling MRI with hypercapnia challenge. Number and volume of lacunes, subcortical hyperintensity volume, microbleeds and normalised brain volume were assessed on MRI. Analysis was exploratory and examined the associations between different markers. Cerebrovascular reactivity measured by ASL correlated with peripheral vasoreactivity measured by flow mediated dilatation. Subjects with ≥5 lacunes were older, with higher carotid intima-media thickness and had impaired cerebral and peripheral vasoreactivity. Subjects with depressive symptoms, disability or delayed processing speed also showed a trend to impaired vasoreactivity. Impaired vasoreactivity and vascular dysfunction may play a significant role in the pathophysiology of CADASIL, and vascular assessments may be useful biomarkers of severity in both longitudinal and clinical trials.

Oxygen challenge magnetic resonance imaging in healthy human volunteers.

Oxygen challenge imaging involves transient hyperoxia applied during deoxyhaemoglobin sensitive (T2*-weighted) magnetic resonance imaging and has the potential to detect changes in brain oxygen extraction. In order to develop optimal practical protocols for oxygen challenge imaging, we investigated the influence of oxygen concentration, cerebral blood flow change, pattern of oxygen administration and field strength on T2*-weighted signal. Eight healthy volunteers underwent multi-parametric magnetic resonance imaging including oxygen challenge imaging and arterial spin labelling using two oxygen concentrations (target FiO2 of 100 and 60%) administered consecutively (two-stage challenge) at both 1.5T and 3T. There was a greater signal increase in grey matter compared to white matter during oxygen challenge (p < 0.002 at 3T, P < 0.0001 at 1.5T) and at FiO2 = 100% compared to FiO2 = 60% in grey matter at both field strengths (p < 0.02) and in white matter at 3T only (p = 0.0314). Differences in the magnitude of signal change between 1.5T and 3T did not reach statistical significance. Reduction of T2*-weighted signal to below baseline, after hyperoxia withdrawal, confounded interpretation of two-stage oxygen challenge imaging. Reductions in cerebral blood flow did not obscure the T2*-weighted signal increases. In conclusion, the optimal protocol for further study should utilise target FiO2 = 100% during a single oxygen challenge. Imaging at both 1.5T and 3T is clinically feasible.

Arterial branching and basal ganglia lacunes: A study in pure small vessel disease.

INTRODUCTION: Lacunes are defined morphologically by size and location, but radiological characteristics alone may be unable to distinguish small vessel disease aetiology from alternative mechanisms. We investigated the branching order of arterial vessels associated with basal ganglia lacunes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), in order to improve the understanding of their pathogenesis in pure cerebral small vessel disease. PATIENTS AND METHODS: Adults with a confirmed diagnosis of CADASIL were included. A pilot study was conducted in a Scottish CADASIL cohort. The Paris-Munich CADASIL cohort was used for independent validation. Lacunes identified on T1-weighted magnetic resonance imaging scans were registered to a standard brain template. A microangiographic template of the basal ganglia vasculature was automatically overlaid onto coronal slices, and raters estimated the vessel branching order related to each lacune. RESULTS: Of 179 lacunes, 150 (84%) were associated with third-order vessels. In 14 incident lacunes, 11 (79%) were associated with third-order vessels. In the pilot study, lacune volume was significantly lower in lacunes associated with third-order vessels (0.04 ml ± 0.04 ml) compared to second-order vessels (0.48 ± 0.16 ml; p < 0.001). DISCUSSION: In this study of CADASIL patients, most lacunes were small and associated with third-order vessel disease. This suggests that these are the vessels primarily affected in cerebral small vessel disease. Microangiographic template techniques could be used to further investigate in a general stroke population whether finding large lacunes originating from higher order vessels indicates an alternative cause of stroke. CONCLUSION: Lacunes in pure small vessel disease are associated with the smallest vessels in the basal ganglia.

Clinicopathological case: progressive cognitive decline with gait disturbance in a steel worker.

A 57-year-old male steel plant worker presented with fatigue and altered liver function tests. Over the next two years, he developed cognitive decline, parkinsonism and seizures. This paper reports the clinicopathological conference at the 37th Edinburgh Advanced Neurology Course 2015 and outlines what we can learn from this case.

Respiratory challenge MRI: Practical aspects.

Respiratory challenge MRI is the modification of arterial oxygen (PaO2) and/or carbon dioxide (PaCO2) concentration to induce a change in cerebral function or metabolism which is then measured by MRI. Alterations in arterial gas concentrations can lead to profound changes in cerebral haemodynamics which can be studied using a variety of MRI sequences. Whilst such experiments may provide a wealth of information, conducting them can be complex and challenging. In this paper we review the rationale for respiratory challenge MRI including the effects of oxygen and carbon dioxide on the cerebral circulation. We also discuss the planning, equipment, monitoring and techniques that have been used to undertake these experiments. We finally propose some recommendations in this evolving area for conducting these experiments to enhance data quality and comparison between techniques.

Resting state connectivity and cognitive performance in adults with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Cognitive impairment is an inevitable feature of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), affecting executive function, attention and processing speed from an early stage. Impairment is associated with structural markers such as lacunes, but associations with functional connectivity have not yet been reported. Twenty-two adults with genetically-confirmed CADASIL (11 male; aged 49.8 ± 11.2 years) underwent functional magnetic resonance imaging at rest. Intrinsic attentional/executive networks were identified using group independent components analysis. A linear regression model tested voxel-wise associations between cognitive measures and component spatial maps, and Pearson correlations were performed with mean intra-component connectivity z-scores. Two frontoparietal components were associated with cognitive performance. Voxel-wise analyses showed an association between one component cluster and processing speed (left middle temporal gyrus; peak -48, -18, -14; ZE = 5.65, pFWE corr = 0.001). Mean connectivity in both components correlated with processing speed (r = 0.45, p = 0.043; r = 0.56, p = 0.008). Mean connectivity in one component correlated with faster Trailmaking B minus A time (r = -0.77, p < 0.001) and better executive performance (r = 0.56, p = 0.011). This preliminary study provides evidence for associations between cognitive performance and attentional network connectivity in CADASIL. Functional connectivity may be a useful biomarker of cognitive performance in this population.

Insular cortex hypoperfusion and acute phase blood glucose after stroke: a CT perfusion study.

BACKGROUND AND PURPOSE: Insular cortex ischemia is proposed to mediate a sympathetic stimulus that leads to acute hyperglycemia after stroke. METHODS: We retrospectively analyzed insular perfusion on perfusion CT (median 180 minutes after onset) in 35 patients. RESULTS: We found no association of hypoperfusion (relative cerebral blood flow <0.51) with early (<6 hours) or delayed (<72 hours) hyperglycemia, or hemispheric lateralization. CONCLUSIONS: Insular cortex hypoperfusion <6 hours after stroke onset was not associated with hyperglycemia.