Infarct Evolution on MR-DWI After Thrombectomy in Acute Stroke Patients Randomized to Nerinetide or Placebo: The REPERFUSE-NA1 Study

BACKGROUND AND OBJECTIVES: 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. METHODS: 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 U test and multiple linear regression. RESULTS: 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 (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. DISCUSSION: 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. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT02930018. CLASSIFICATION OF EVIDENCE: 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.

Arterial spin labelling reveals multi-regional cerebral hypoperfusion in patients with transient ischemic attack that are unrelated to ischemia location: A proof-of-concept study.

Background and Aims: Patients with transient ischemic attack (TIA) have a substantially increased risk of early dementia. In this exploratory study, we aim to determine whether patients with TIA have 1) measurable regional cerebral hypoperfusion unrelated to the location of ischemia, and 2) determine the relationship of regional cerebral blood flow (rCBF) with their cognitive profiles. Methods: Patients with TIA (N = 49) and seventy-nine (N = 79) age and sex matched controls underwent formal neuropsychological testing and MRI. Quantitative arterial spin labelling rCBF maps (mL/min/100 g) were registered to the corresponding high resolution T1-weighted image. Linear regression was used to determine the association between demographic, clinical and cognitive variables and rCBF. Results: Patients with TIA had significantly (p < 0.05) lower cognitive scores in the MMSE, MOCA, ACE-R, WAIS-IV DS Coding and Trail Making Tests A and B compared to controls. TIA patients had significantly lower rCBF in the left entorhinal cortex (p = 0.03), right posterior cingulate (p = 0.04), and right precuneus (p = 0.05), after adjusting for age and sex, that were unrelated to the regional anatomical volume and DWI positivity. Regional hypoperfusion in the right posterior cingulate and right precuneus was associated with impaired visual memory (BVMT total, p = 0.05 for both regions) and slower processing speed (TMT A, p = 0.04 and p = 0.01), respectively after adjusting for age and sex. Conclusions: TIA patients have patterns of regional hypoperfusion in multiple cortical regions unrelated to the parcellated regional anatomical volume or the presence of a DWI lesion. Regional hypoperfusion in patients with TIA may be an early marker conferring risk of future cognitive decline that needs to be confirmed by future studies.

Acute stroke imaging selection for mechanical thrombectomy in the extended time window: is it time to go back to basics? A review of current evidence.

Treatment with endovascular therapy in the extended time window for acute ischaemic stroke with large vessel occlusion involves stringent selection criteria based on the two landmark studies DAWN and DEFUSE3. Current protocols typically include the requirement of advanced perfusion imaging which may exclude a substantial proportion of patients from receiving a potentially effective therapy. Efforts to offer endovascular reperfusion therapies to all appropriate candidates may be facilitated by the use of simplified imaging selection paradigms with widely available basic imaging techniques, such as non-contrast CT and CT angiography. Currently available evidence from our literature review suggests that patients meeting simplified imaging selection criteria may benefit as much as those patients selected using advanced imaging techniques (CT perfusion or MRI) from endovascular therapy in the extended time window. A comprehensive understanding of the role of imaging in patient selection is critical to optimising access to endovascular therapy in the extended time window and improving outcomes in acute stroke. This article provides an overview on current developments and future directions in this emerging area.

White matter tract microstructure and cognitive performance after transient ischemic attack.

BACKGROUND AND PURPOSE: Patients with transient ischemic attack (TIA) show evidence of cognitive impairment but the reason is not clear. Measurement of microstructural changes in white matter (WM) using diffusion tensor imaging (DTI) may be a useful outcome measure. We report WM changes using DTI and the relationship with neuropsychological performance in a cohort of transient ischemic attack (TIA) and non-TIA subjects. METHODS: Ninety-five TIA subjects and 51 non-TIA subjects were assessed using DTI and neuropsychological batteries. Fractional anisotropy (FA) and mean diffusivity (MD) maps were generated and measurements were collected from WM tracts. Adjusted mixed effects regression modelled the relationship between groups and DTI metrics. RESULTS: Transient ischemic attack subjects had a mean age of 67.9 ± 9.4 years, and non-TIA subjects had a mean age 64.9 ± 9.9 years. The TIA group exhibited higher MD values in the fornix (0.36 units, P < 0.001) and lower FA in the superior longitudinal fasciculus (SLF) (-0.29 units, P = 0.001), genu (-0.22 units, P = 0.016), and uncinate fasciculus (UF) (-0.26 units, P = 0.004). Compared to non-TIA subjects, subjects with TIA scored lower on the Addenbrooke's Cognitive Assessment-Revised (median score 95 vs 91, P = 0.01) but showed no differences in scores on the Montreal Cognitive Assessment (median 27 vs 26) or the Mini-Mental State Examination (median 30). TIA subjects had lower scores in memory (median 44 vs 52, P < 0.01) and processing speed (median 45 vs 62, P < 0.01) but not executive function, when compared to non-TIA subjects. Lower FA and higher MD in the fornix, SLF, and UF were associated with poorer performance on tests of visual memory and executive function but not verbal memory. Lower FA in the UF and fornix were related to higher timed scores on the TMT-B (P < 0.01), and higher SLF MD was related to higher scores on TMT-B (P < 0.01), confirming worse executive performance in the TIA group. CONCLUSIONS: DTI scans may be useful for detecting microstructural disease in TIA subjects before cognitive symptoms develop. DTI parameters, white matter hyperintensities, and vascular risk factors underly some of the altered neuropsychological measures in TIA subjects.

Defining reperfusion post endovascular therapy in ischemic stroke using MR-dynamic contrast enhanced perfusion.

OBJECTIVES: Cerebral blood flow (CBF) measurements after endovascular therapy (EVT) for acute ischemic stroke are important to distinguish early secondary injury related to persisting ischemia from that related to reperfusion when considering clinical response and infarct growth. METHODS: We compare reperfusion quantified by the modified Thrombolysis in Cerebral Infarction Score (mTICI) with perfusion measured by MRI dynamic contrast-enhanced perfusion within 5 h of EVT anterior circulation stroke. MR perfusion (rCBF, rCBV, rTmax, rT0) and mTICI scores were included in a predictive model for change in NIHSS at 24 h and diffusion-weighted imaging (DWI) lesion growth (acute to 24 h MRI) using a machine learning RRELIEFF feature selection coupled with a support vector regression. RESULTS: For all perfusion parameters, mean values within the acute infarct for the TICI-2b group (considered clinically good reperfusion) were not significantly different from those in the mTICI <2b (clinically poor reperfusion). However, there was a statistically significant difference in perfusion values within the acute infarct region of interest between the mTICI-3 group versus both mTICI-2b and <2b (p = 0.02). The features that made up the best predictive model for change in NIHSS and absolute DWI lesion volume change was rT0 within acute infarct ROI and admission CTA collaterals respectively. No other variables, including mTICI scores, were selected for these best models. The correlation coefficients (Root mean squared error) for the cross-validation were 0.47 (13.7) and 0.51 (5.7) for change in NIHSS and absolute DWI lesion volume change. CONCLUSION: MR perfusion following EVT provides accurate physiological approach to understanding the relationship of CBF, clinical outcome, and DWI growth. ADVANCES IN KNOWLEDGE: MR perfusion CBF acquired is a robust, objective reperfusion measurement providing following recanalization of the target occlusion which is critical to distinguish potential therapeutic harm from the failed technical success of EVT as well as improve the responsiveness of clinical trial outcomes to disease modification.

Automatic arterial input function selection in CT and MR perfusion datasets using deep convolutional neural networks.

PURPOSE: The computation of perfusion parameter images requires knowledge of the arterial blood flow in the form of an arterial input function (AIF). This work proposes a novel method to automatically identify AIFs in computed tomography perfusion (CTP) and dynamic susceptibility contrast perfusion-weighted MRI (PWI) datasets using a deep convolutional neural network (CNN). METHODS: One-hundred CTP and 100 PWI datasets of acute ischemic stroke patients were available for model development and evaluation. For each modality, 50 datasets were used for CNN training and 20 for validation using manually selected AIFs and non-arterial tissue concentration time curves. Model evaluation was performed using the remaining 30 independent validation datasets from each modality with manual AIF selections provided by two experts as ground truth. Additionally, AIFs were also extracted using an established automatic shape-based algorithm for comparison purposes. The extracted AIFs were compared using normalized cross-correlation and shape features as well as using the Dice similarity metric and volume of the corresponding hypoperfusion (Tmax > 6 s) lesions. RESULTS: The cross-correlation values comparing the manual AIFs and those extracted by the proposed CNN method were significantly greater than those comparing the manual AIFs to the shape-based comparison method. Likewise, hypoperfusion lesions generated using the manually selected AIFs and CNN-based AIFs showed higher Dice values compared to hypoperfusion lesions generated using the comparison AIF extraction method. Shape features for AIFs generated by the proposed method did not differ significantly from the manual AIFs, with the exception that the CNN-derived AIFs for the PWI datasets showed marginally greater peak heights. CONCLUSION: Deep convolutional neural network models are viable for the automatic extraction of the AIF from CTP and PWI datasets.

Recanalization following Endovascular treatment and imaging of PErfusion, Regional inFarction and atrophy to Understand Stroke Evolution-NA1 (REPERFUSE-NA1).

RATIONALE: Following endovascular treatment, poor clinical outcomes are more frequent if the initial infarct core or volume of irreversible brain damage is large. Clinical outcomes may be improved using neuroprotective agents that reduce stroke volume and improve recovery. AIM: The aim of the REPERFUSE NA1 was to replicate the preclinical neuroprotection study that significantly reduced infarct volume in a primate model of ischemia reperfusion. Specifically, REPERFUSE NA1 will determine if administration of the neuroprotectant NA1 prior to endovascular therapy can significantly reduce early (Day 2 subtract Day 1 diffusion-weighted imaging volume) and delayed secondary infarct (90-day whole brain atrophy plus FLAIR volume-Day 1 diffusion-weighted imaging volume) growth, as measured by magnetic resonance imaging. METHODS AND DESIGN: REPERFUSE-NA1 is a magnetic resonance imaging observational substudy of ESCAPE-NA1 (ClinicalTrialGov NCT02930018). A total of 150 acute stroke patients will be recruited (including 20% attrition) that have been randomized to either NA1 or placebo in the ESCAPE-NA1 trial. STUDY OUTCOMES: Primary-Early infarct growth measured using diffusion-weighted imaging will be at least 30% smaller in patients receiving NA1 compared to placebo. Secondary-Delayed secondary stroke injury at 90 days will be significantly reduced in patients receiving NA1 compared to placebo, as well as delayed secondary growth at 90 days. CONCLUSION: REPERFUSE-NA1 will demonstrate the effect of NA1 neuroprotection on reducing the early and delayed stroke injury after reperfusion treatment.

Temporal evolution and spatial distribution of quantitative T2 MRI following acute ischemia reperfusion injury.

BACKGROUND: Determining mechanisms of secondary stroke injury related to cerebral blood flow and the severity of microvascular injury contributing to edema and blood-brain barrier breakdown will be critical for the development of adjuvant therapies for revascularization treatment. AIM: To characterize the heterogeneity of the ischemic lesion using quantitative T2 imaging along with diffusion-weighted magnetic resonance imaging (DWI) within five hours of treatment. METHODS: Quantitative T2 magnetic resonance imaging was acquired within 5 h (baseline) and at 24 h (follow-up) of stroke treatment in 29 patients. Dynamic contrast enhanced permeability imaging was performed at baseline in a subgroup of patients. Absolute volume change and lesion percent change was determined for the quantitative T2, DWI, and absolute volume change sequences. A Gaussian process with RRELIEFF feature selection algorithm was used for prediction of relative quantitative T2 and DWI lesion growth, baseline and follow-up quantitative T2/DWI lesion ratios, and also NIHSS at 24 h and change in NIHSS from admission to 24 h. RESULTS: In n = 27 patients, median (interquartile range) lesion percent change was 114.8% (48.9%, 259.1%) for quantitative T2, 48.2% (-12.6%, 179.6%) for absolute volume change, and 62.7% (26.3%, 230.9%) for DWI, respectively. Our model, consisting of baseline NIHSS, CT ASPECTS, and systolic blood pressure, showed a strong correlation with quantitative T2 percent change (cross correlation R2 = 0.80). There was a strong predictive ability for quantitative T2/DWI lesion ratio at 24 h using baseline NIHSS and last seen normal to 24 h magnetic resonance imaging time (cross correlation R2 = 0.93). Baseline dynamic contrast enhanced permeability was moderately correlated to the baseline quantitative T2 values (rho = 0.38). CONCLUSION: Quantitative T2 imaging provides critical information for development of therapeutic approaches that could ameliorate microvascular damage during ischemia reperfusion.

Correction to: Accuracy and Reliability of Multiphase CTA Perfusion for Identifying Ischemic Core.

Correction to: Clin Neuroradiol 2018 https://doi.org/10.1007/s00062-018-0717-x Unfortunately, the author list of the original version of this article contains a mistake. The middle name of the author "Rani Gupta Sah" was erroneously tagged as part of the surname in the article's metadata.This mistake.

Longitudinal Brain Atrophy Rates in Transient Ischemic Attack and Minor Ischemic Stroke Patients and Cognitive Profiles.

Introduction: Patients with transient ischemic attack (TIA) and minor stroke demonstrate cognitive impairment, and a four-fold risk of late-life dementia. Aim: To study the extent to which the rates of brain volume loss in TIA patients differ from healthy controls and how they are correlated with cognitive impairment. Methods: TIA or minor stroke patients were tested with a neuropsychological battery and underwent T1 weighted volumetric magnetic resonance imaging scans at fixed intervals over a 3 years period. Linear mixed effects regression models were used to compare brain atrophy rates between groups, and to determine the relationship between atrophy rates and cognitive function in TIA and minor stroke patients. Results: Whole brain atrophy rates were calculated for the TIA and minor stroke patients; n = 38 between 24 h and 18 months, and n = 68 participants between 18 and 36 months, and were compared to healthy controls. TIA and minor stroke patients demonstrated a significantly higher whole brain atrophy rate than healthy controls over a 3 years interval (p = 0.043). Diabetes (p = 0.012) independently predicted higher atrophy rate across groups. There was a relationship between higher rates of brain atrophy and processing speed (composite P = 0.047 and digit symbol coding P = 0.02), but there was no relationship with brain atrophy rates and memory or executive composite scores or individual cognitive tests for language (Boston naming, memory recall, verbal fluency or Trails A or B score). Conclusion: TIA and minor stroke patients experience a significantly higher rate of whole brain atrophy. In this cohort of TIA and minor stroke patients changes in brain volume over time precede cognitive decline.

Diffusion-Weighted MRI Stroke Volume Following Recanalization Treatment is Threshold-Dependent.

PURPOSE: Infarct lesion segmentation has been problematic as there are a wide range of relative and absolute diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) thresholds that have been used for this purpose. We examined differences of stroke lesion volume and evolution evaluated by magnetic resonance imaging (MRI) during the immediate post-treatment phase (<5 h) and at 24 h. METHODS: In this study 33 acute ischemic stroke patients were imaged with MRI <5 h and 24 h post-reperfusion treatment. Lesion volumes were segmented on ADC maps and average DWI using literature cited absolute ADC and relative DWI thresholds. The segmented lesion volumes within both time points were compared and the absolute change in lesion volume (infarct growth) between the two time points was calculated and compared using Bland-Altman analysis. RESULTS: Lesion volumes differed significantly when different relative DWI or absolute ADC thresholds were used (p < 0.05), which held true for baseline as well as follow-up lesions. The median absolute changes in lesion volume from baseline to follow-up for ADC thresholds of 550 × 10-6 mm2/s, 600 × 10-6 mm2/s, 630 × 10-6 mm2/s and 650 × 10-6 mm2/s were 3.5 ml, 4.2 ml, 4.5 ml, and 6.5 ml, respectively (p < 0.05). Likewise, the median absolute changes in lesion volume from baseline to follow-up for DWI thresholds, k = 0.85, 1.28, 1.64, 1.96, and 2.7 were 10.1 ml, 7.3 ml, 5.7 ml, 5.4 ml and 4.2 ml, respectively (p < 0.05). CONCLUSION: Absolute lesion volumes and changes in lesion volumes (infarct growth) measured after recanalization treatment were dependent on absolute ADC and relative DWI thresholds, which may have clinical significance. Standardization of techniques for measuring DWI lesion volumes requires immediate attention.

Diffusion-weighted imaging lesion growth occurs despite recanalization in acute ischemic stroke: Implications for future treatment trials.

BACKGROUND: A proportion of patients presenting with acute small ischemic strokes have poor functional outcomes, even following rapid recanalization treatment. AIMS: Infarct growth may occur even after successful recanalization and could represent an appropriate endpoint for future stroke therapy trials. METHODS: Magnetic resonance diffusion-weighted imaging lesion volumes were obtained at 5 h (initial posttreatment) and 24 h (follow-up) after acute stroke treatment for n = 33 in ischemic stroke patients. Sample sizes per arm (90% power, 30% effect size) for diffusion-weighted imaging lesion growth between initial and 24 h, early change in the National Institutes of Health Stroke Scale between pre- and 24 h, National Institutes of Health Stroke Scale at 24 h, and diffusion-weighted imaging lesion volume at 24 h were estimated to power a placebo-controlled stroke therapy trial. RESULTS: For patients with poor recanalization (modified thrombolysis in cerebral infarction <2 a; modified arterial occlusion lesion = 0-2) (n = 11), the median diffusion-weighted imaging lesion growth was 8.1 (interquartile range: 4.5, 22.4) ml and with good recanalization (modified thrombolysis in cerebral infarction =2 b or 3; modified arterial occlusion lesion = 3) (n = 22), the median diffusion-weighted imaging lesion growth was 10.0 (interquartile range: 6.0, 28.2) ml ( P = 0.749). When considering a 30% effect size, the sample size required per arm to achieve significance in an acute stroke study would be: (1) N = 49 for the diffusion-weighted imaging lesion growth between initial posttreatment and follow-up time points, (2) N = 65 for the change in the National Institutes of Health Stroke Scale between admission and 24 h, (3) N = 259 for the National Institutes of Health Stroke Scale at 24 h, and (4) N = 256 for diffusion-weighted imaging volume at 24 h. CONCLUSION: Despite best efforts to recanalize the ischemic brain, early diffusion-weighted imaging lesion growth still occurs. Treatment trials in stroke should consider early diffusion-weighted imaging lesion growth as a surrogate outcome measure to significantly reduce sample sizes.

Accuracy and Reliability of Multiphase CTA Perfusion for Identifying Ischemic Core.

PURPOSE: Acute stroke treatment requires simple, quick and accurate detection of early ischemic changes to facilitate treatment decisions guided by published selection criteria. The aim of this study was to determine the accuracy and reliability of multiphase computed tomography angiography (mCTA) perfusion hypoattenuation for detecting early severe ischemia. METHODS: Non-contrast CT (NCCT), mCTA for regional leptomeningeal score (mCTA-rLMC), and mCTA perfusion lesion visibility (mCTA-arterial and mCTA-venous) were assessed blinded to clinical information in patients treated with endovascular therapy (EVT). The extent of early ischemia defined by regions of hypoattenuation was evaluated by the Alberta Stroke Program Early CT Score (ASPECTS). The ASPECTS scores were dichotomized based on the American Heart Association (AHA) guidelines for EVT selection, ASPECTS ≥6 vs. <6. The diagnostic accuracy was calculated by comparison to 24-h magnetic resonance imaging (MRI) or CT ASPECTS. Inter-observer reliability of NCCT and mCTA ASPECTS was evaluated. Machine learning models were used to predict the clinical follow-up outcome, e.g. National Institutes of Health Stroke scale (NIHSS) and modified Rankin scale (mRS) from baseline imaging data and patient information. RESULTS: A total of 89 acute stroke patients (68 ± 15 years of age) were analyzed (33 TICI-0, 56 TICI-2b or 3). Median baseline NIHSS was 17. The mCTA-venous had a large effect on accurately identifying early ischemia when dichotomized for ASPECTS ≥6 vs <6 (likelihood ratio [LR+] > 10 vs. [LR-] < 0.29) compared to the moderate effect of NCCT ([LR+] = 6.7; [LR-] = 0.56) and mCTA-rLMC [(LR+ = 8.0; (LR-) = 0.83)]. The inter-observer reliability in mCTA-venous was almost perfect for all ASPECTS regions except the internal capsule. The machine learning support factor regression model identified mCTA-venous as the most important imaging covariate for predicting 24-h NIHSS and 90-day mRS. CONCLUSION: The assessment of mCTA-venous permits a more accurate detection of early ischemia than NCCT and mCTA-rLMC score and is predictive of clinical outcome. We would recommend the inclusion of mCTA perfusion lesion in future endovascular trials aiming at extending current AHA guidelines for EVT in stroke patients with low ASPECTS.

Absolute risk and predictors of the growth of acute spontaneous intracerebral haemorrhage: a systematic review and meta-analysis of individual patient data.

BACKGROUND: Intracerebral haemorrhage growth is associated with poor clinical outcome and is a therapeutic target for improving outcome. We aimed to determine the absolute risk and predictors of intracerebral haemorrhage growth, develop and validate prediction models, and evaluate the added value of CT angiography. METHODS: In a systematic review of OVID MEDLINE-with additional hand-searching of relevant studies' bibliographies- from Jan 1, 1970, to Dec 31, 2015, we identified observational cohorts and randomised trials with repeat scanning protocols that included at least ten patients with acute intracerebral haemorrhage. We sought individual patient-level data from corresponding authors for patients aged 18 years or older with data available from brain imaging initially done 0·5-24 h and repeated fewer than 6 days after symptom onset, who had baseline intracerebral haemorrhage volume of less than 150 mL, and did not undergo acute treatment that might reduce intracerebral haemorrhage volume. We estimated the absolute risk and predictors of the primary outcome of intracerebral haemorrhage growth (defined as >6 mL increase in intracerebral haemorrhage volume on repeat imaging) using multivariable logistic regression models in development and validation cohorts in four subgroups of patients, using a hierarchical approach: patients not taking anticoagulant therapy at intracerebral haemorrhage onset (who constituted the largest subgroup), patients taking anticoagulant therapy at intracerebral haemorrhage onset, patients from cohorts that included at least some patients taking anticoagulant therapy at intracerebral haemorrhage onset, and patients for whom both information about anticoagulant therapy at intracerebral haemorrhage onset and spot sign on acute CT angiography were known. FINDINGS: Of 4191 studies identified, 77 were eligible for inclusion. Overall, 36 (47%) cohorts provided data on 5435 eligible patients. 5076 of these patients were not taking anticoagulant therapy at symptom onset (median age 67 years, IQR 56-76), of whom 1009 (20%) had intracerebral haemorrhage growth. Multivariable models of patients with data on antiplatelet therapy use, data on anticoagulant therapy use, and assessment of CT angiography spot sign at symptom onset showed that time from symptom onset to baseline imaging (odds ratio 0·50, 95% CI 0·36-0·70; p<0·0001), intracerebral haemorrhage volume on baseline imaging (7·18, 4·46-11·60; p<0·0001), antiplatelet use (1·68, 1·06-2·66; p=0·026), and anticoagulant use (3·48, 1·96-6·16; p<0·0001) were independent predictors of intracerebral haemorrhage growth (C-index 0·78, 95% CI 0·75-0·82). Addition of CT angiography spot sign (odds ratio 4·46, 95% CI 2·95-6·75; p<0·0001) to the model increased the C-index by 0·05 (95% CI 0·03-0·07). INTERPRETATION: In this large patient-level meta-analysis, models using four or five predictors had acceptable to good discrimination. These models could inform the location and frequency of observations on patients in clinical practice, explain treatment effects in prior randomised trials, and guide the design of future trials. FUNDING: UK Medical Research Council and British Heart Foundation.

A longitudinal magnetic resonance imaging study of neurodegenerative and small vessel disease, and clinical cognitive trajectories in non demented patients with transient ischemic attack: the PREVENT study.

BACKGROUND: Late-life cognitive decline, caused by progressive neuronal loss leading to brain atrophy years before symptoms are detected, is expected to double in Canada over the next two decades. Cognitive impairment in late life is attributed to vascular and lifestyle related risk factors in mid-life in a substantial proportion of cases (50%), thereby providing an opportunity for effective prevention of cognitive decline if incipient disease is detected earlier. Patients presenting with transient ischemic attack (TIA) commonly display some degree of cognitive impairment and are at a 4-fold increased risk of dementia. In the Predementia Neuroimaging of Transient Ischemic Attack (PREVENT) study, we will address what disease processes (i.e., Alzheimer's vs. vascular disease) lead to neurodegeneration, brain atrophy, and cognitive decline, and whether imaging measurements of brain iron accumulation using quantitative susceptibility mapping predicts subsequent brain atrophy and cognitive decline. METHODS: A total of 440 subjects will be recruited for this study with 220 healthy subjects and 220 TIA patients. Early Alzheimer's pathology will be determined by cerebrospinal fluid samples (including tau, a marker of neuronal injury, and amyloid ß1-42) and by MR measurements of iron accumulation, a marker for Alzheimer's-related neurodegeneration. Small vessel disease will be identified by changes in white matter lesion volume. Predictors of advanced rates of cerebral and hippocampal atrophy at 1 and 3 years will include in vivo Alzheimer's disease pathology markers, and MRI measurements of brain iron accumulation and small vessel disease. Clinical and cognitive function will be assessed annually post-baseline for a period of 5-years using a clinical questionnaire and a battery of neuropsychological tests, respectively. DISCUSSION: The PREVENT study expects to demonstrate that TIA patients have increased early progressive rates of cerebral brain atrophy after TIA, before cognitive decline can be clinically detected. By developing and optimizing high-level machine learning models based on clinical data, image-based (quantitative susceptibility mapping, regional brain, and white matter lesion volumes) features, and cerebrospinal fluid biomarkers, PREVENT will provide a timely opportunity to identify individuals at greatest risk of late-life cognitive decline early in the course of disease, supporting future therapeutic strategies for the promotion of healthy aging.

Neurovascular Unit: Basic and Clinical Imaging with Emphasis on Advantages of Ferumoxytol.

Physiological and pathological processes that increase or decrease the central nervous system's need for nutrients and oxygen via changes in local blood supply act primarily at the level of the neurovascular unit (NVU). The NVU consists of endothelial cells, associated blood-brain barrier tight junctions, basal lamina, pericytes, and parenchymal cells, including astrocytes, neurons, and interneurons. Knowledge of the NVU is essential for interpretation of central nervous system physiology and pathology as revealed by conventional and advanced imaging techniques. This article reviews current strategies for interrogating the NVU, focusing on vascular permeability, blood volume, and functional imaging, as assessed by ferumoxytol an iron oxide nanoparticle.

Collateral Scoring on CT Angiogram Must Evaluate Phase and Regional Pattern.

PURPOSE: We measured anterior cerebral artery (ACA)-middle cerebral artery (MCA) and posterior cerebral artery (PCA)-MCA pial filling on single-phase computed tomography angiograms (sCTAs) in acute ischemic stroke and correlate with the CTA-based Massachusetts General Hospital (MGH) and digital subtraction angiography (DSA)-based American Society of Interventional and Therapeutic Neuroradiology (ASITN) score. METHODS: Patients with acute stroke and M1 MCA±intracranial internal carotid artery occlusion on baseline CTA were included. Baseline sCTA was assessed for phase of image acquisition. An evaluator assessed collaterals using the Calgary Collateral (CC) Score (measures pial arterial filling in ACA-MCA and PCA-MCA regions separately), the CTA-based MGH score, and on DSA using the ASITN score. Infarct volumes were measured on 24- to 48-hour magnetic resonance imaging/ computed tomography. RESULTS: Of 106 patients, baseline sCTA was acquired in early arterial phase in 9.9%, peak arterial in 50.7%, equilibrium in 32.4%, early venous in 5.6%, and late venous in 1.4%. Variance in ACA-MCA collaterals explained only 32% of variance in PCA-MCA collaterals on the CC score (Spearman's correlation coefficient rho [rho]=0.56). Correlation between ACA-MCA collaterals and the MGH score was strong (rho=0.8); correlation between PCA-MCA collaterals and this score was modest (rho=0.54). Correlation between ACA-MCA collaterals and the ASITN score was modest (n=53, rho=0.43); and correlation between PCA-MCA collaterals and ASITN score was poor (rho=0.33). Of the CTA-based scores, the CC Score (Akaike [AIC] 1022) was better at predicting follow-up infarct volumes than was the MGH score (AIC 1029). CONCLUSION: Collateral assessments in acute ischemic stroke are best done using CTA with temporal resolution and by assessing regional variability. ACA-MCA and MCA-PCA collaterals should be evaluated separately.

Use of Noncontrast Computed Tomography and Computed Tomographic Perfusion in Predicting Intracerebral Hemorrhage After Intravenous Alteplase Therapy.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage is a feared complication of intravenous alteplase therapy in patients with acute ischemic stroke. We explore the use of multimodal computed tomography in predicting this complication. METHODS: All patients were administered intravenous alteplase with/without intra-arterial therapy. An age- and sex-matched case-control design with classic and conditional logistic regression techniques was chosen for analyses. Outcome was parenchymal hemorrhage on 24- to 48-hour imaging. Exposure variables were imaging (noncontrast computed tomography hypoattenuation degree, relative volume of very low cerebral blood volume, relative volume of cerebral blood flow ≤7 mL/min·per 100 g, relative volume of Tmax ≥16 s with all volumes standardized to z axis coverage, mean permeability surface area product values within Tmax ≥8 s volume, and mean permeability surface area product values within ipsilesional hemisphere) and clinical variables (NIHSS [National Institutes of Health Stroke Scale], onset to imaging time, baseline systolic blood pressure, blood glucose, serum creatinine, treatment type, and reperfusion status). RESULTS: One-hundred eighteen subjects (22 patients with parenchymal hemorrhage versus 96 without, median baseline NIHSS score of 15) were included in the final analysis. In multivariable regression, noncontrast computed tomography hypoattenuation grade (P<0.006) and computerized tomography perfusion white matter relative volume of very low cerebral blood volume (P=0.04) were the only significant variables associated with parenchymal hemorrhage on follow-up imaging (area under the curve, 0.73; 95% confidence interval, 0.63-0.83). Interrater reliability for noncontrast computed tomography hypoattenuation grade was moderate (κ=0.6). CONCLUSIONS: Baseline hypoattenuation on noncontrast computed tomography and very low cerebral blood volume on computerized tomography perfusion are associated with development of parenchymal hemorrhage in patients with acute ischemic stroke receiving intravenous alteplase.

Regional Comparison of Multiphase Computed Tomographic Angiography and Computed Tomographic Perfusion for Prediction of Tissue Fate in Ischemic Stroke.

BACKGROUND AND PURPOSE: Within different brain regions, we determine the comparative value of multiphase computed tomographic angiography (mCTA) and computed tomographic perfusion (CTP) in predicting follow-up infarction. METHODS: Patients with M1-middle cerebral artery occlusions were prospectively included in this multicenter study. Regional analysis was performed for each patient within Alberta Stroke Program Early CT Score regions M2 to M6. Regional pial vessel filling was assessed on mCTA in 3 ways: (1) Washout of contrast within pial vessels; (2) Extent of maximal pial vessel enhancement compared with contralateral hemisphere; (3) Delay in maximal pial vessel enhancement compared with contralateral hemisphere. Cerebral blood flow, cerebral blood volume, and Tmax data were extracted within these Alberta Stroke Program Early CT Score regions. Twenty-four- to 36-hour magnetic resonance imaging/CT was assessed for infarct in each Alberta Stroke Program Early CT Score region (defined as >20% infarction within that region). Mixed effects logistic regression models were used to compare mCTA and CTP parameters when predicting brain infarction. Area under the receiver operating characteristics was used to assess discriminative value of statistical models. RESULTS: Seventy-seven patients were included. mCTA parameter washout and CTP parameter Tmax were significantly associated with follow-up infarction in all models (P<0.05). The area under the receiver operating characteristic for mCTA models ranged from 92% to 94% and was not different compared with all CTP models (P>0.05). Mean Tmax and cerebral blood volume values were significantly different between each washout score (P<0.01) and each delay score category (P<0.01). Mean Tmax, cerebral blood flow, and cerebral blood volume values were significantly different between each extent score category (P<0.05). CONCLUSIONS: Similar to CTP, multiphase CTA can be used to predict tissue fate regionally in acute ischemic stroke patients.