Article

Transient and permanent resolution of ischemic lesions on diffusion-weighted imaging after brief periods of focal ischemia in rats : correlation with histopathology

February 2001

February 2001

Authors:

BACKGROUND AND PURPOSE: The early ischemic lesions demonstrated by diffusion-weighted imaging (DWI) are potentially reversible. The purposes of this study were to determine whether resolution of initial DWI lesions is transient or permanent after different brief periods of focal brain ischemia and to evaluate histological outcomes. METHODS: Sixteen rats were subjected to 10 minutes (n=7) or 30 minutes (n=7) of temporary middle cerebral artery occlusion or sham operation (n=2). DWI, perfusion-weighted imaging (PWI), and T(2)-weighted imaging (T(2)WI) were performed during occlusion; immediately after reperfusion; and at 0.5, 1.0, 1.5, 12, 24, 48, and 72 hours after reperfusion. After the last MRI study, the brains were fixed, sectioned, stained with hematoxylin and eosin, and evaluated for neuronal necrosis. RESULTS: No MRI or histological abnormalities were observed in the sham-operated rats. In both the 10-minute and 30-minute groups, the perfusion deficits and DWI hyperintensities that occurred during occlusion disappeared shortly after reperfusion. The DWI, PWI, and T(2)WI results remained normal thereafter in the 10-minute group, whereas secondary DWI hyperintensity and T(2)WI abnormalities developed at the 12-hour observation point in the 30-minute group. Histological examinations demonstrated neuronal necrosis in both groups, but the number of necrotic neurons was significantly higher in the 30-minute group (95+/-4%) than in the 10-minute group (17+/-10%, P

Sustained diffusion reversal with in-bore reperfusion in monkey stroke models: Confirmed by prospective magnetic resonance imaging

Article

Full-text available

Jul 2016

Although early diffusion lesion reversal after recanalization treatment of acute ischaemic stroke has been observed in clinical settings, the reversibility of lesions observed by diffusion-weighted imaging remains controversial. Here, we present consistent observations of sustained diffusion lesion reversal after transient middle cerebral artery occlusion in a monkey stroke model. Seven rhesus macaques were subjected to endovascular transient middle cerebral artery occlusion with in-bore reperfusion confirmed by repeated prospective diffusion-weighted imaging. Early diffusion lesion reversal was defined as lesion reversal at 3 h after reperfusion. Sustained diffusion lesion reversal was defined as the difference between the ADC-derived pre-reperfusion maximal ischemic lesion volume (ADCD-P Match) and the lesion on 4-week follow-up FLAIR magnetic resonance imaging. Diffusion lesions were spatiotemporally assessed using a 3-D voxel-based quantitative technique. The ADCD-P Match was 9.7 ± 6.0% (mean ± SD) and the final infarct was 1.2–6.0% of the volume of the ipsilateral hemisphere. Early diffusion lesion reversal and sustained diffusion lesion reversal were observed in all seven animals, and the calculated percentages compared with their ADCD-P Match ranged from 8.3 to 51.9% (mean ± SD, 26.9 ± 15.3%) and 41.7–77.8% (mean ± SD, 65.4 ± 12.2%), respectively. Substantial sustained diffusion lesion reversal and early reversal were observed in all animals in this monkey model of transient focal cerebral ischaemia.

How Sustained Is 24-Hour Diffusion-Weighted Imaging Lesion Reversal?: Serial Magnetic Resonance Imaging in a Patient Cohort Thrombolyzed Within 4.5 Hours of Stroke Onset

Article

Feb 2015

Here, we assessed how sustained is reversal of the acute diffusion lesion (RAD) observed 24 hours after intravenous thrombolysis, and the relationships between RAD fate and early neurological improvement. We analyzed 155 consecutive patients thrombolyzed intravenously 152 minutes (median) after stroke onset and who underwent 3 MR sessions: 1 before and 2 after treatment (median times from onset, 25.6 and 54.3 hours, respectively). Using voxel-based analysis of diffusion-weighted imaging (DWI)1, DWI2, and DWI3 lesions on coregistered image data sets, we assessed the outcome of RAD voxels (hyperintense on DWI1 but not on DWI2) as transient or sustained on DWI3, and their relationships with early neurological improvement, defined as ΔNational Institutes of Health Stroke Scale ≥8 or National Institutes of Health Stroke Scale ≤1 at 24 hours. Tmax and apparent diffusion coefficient values were compared between sustained and transient RAD voxels. The median (interquartile range) baseline National Institutes of Health Stroke Scale and DWI1 lesion volume were 11 (7-18) mL and 15.6 (6.0-50.9) mL, respectively. The median (interquartile range) RAD volume on DWI2 was 2.8 (1.1-6.6) mL, of which 70% was sustained on DWI3. Sixteen (10.3%) patients had sustained RAD ≥10 mL. As compared with transient RAD voxels, sustained RAD voxels had nonsignificantly higher baseline apparent diffusion coefficient values (median [interquartile range], 793 [717-887] versus 777 [705-869]×10(-6) mm(2)·s (-1), respectively; P=0.08) and significantly better perfusion (Tmax, mean±SD, 6.3±3.2 versus 7.8±4.0 s; P<0.001). At variance with transient RAD, the volume of sustained RAD was associated with early neurological improvement in multivariate analysis (odds ratio, 1.08; 95% confidence interval, [1.01-1.17], per 1-mL increase; P=0.03). After thrombolysis, over two-thirds of the DWI lesion reversal captured on 24-hour follow-up MR is sustained. Sustained DWI lesion reversal volume is a strong imaging correlate of early neurological improvement. © 2015 American Heart Association, Inc.

Association of Iatrogenic Infarcts With Clinical and Cognitive Outcomes in the Evaluating Neuroprotection in Aneurysm Coiling Therapy Trial

Article

Feb 2022
NEUROLOGY

Background: Small iatrogenic brain infarcts are often seen on diffusion-weighted MRI (DWI) following surgical or endovascular procedures, but there are few data on their clinical effects. We examined the association of iatrogenic infarcts with outcomes in the ENACT (Evaluating Neuroprotection in Aneurysm Coiling Therapy) randomized-controlled trial of nerinetide in patients undergoing endovascular repair of intracranial aneurysms. Methods: In this post-hoc analysis, we used multi-variable models to evaluate the association of the presence and number of iatrogenic infarcts on DWI with neurological impairment (National Institutes of Health Stroke Scale[NIHSS]), functional status (modified Rankin Scale[mRS]), cognitive and neuropsychiatric outcomes (30-minute test battery) at 1-4 days and 30-days post-procedure. We also related infarct number to a Z-score-derived composite outcome score using quantile regression. Results: Among 184 patients (median age 56,IQR 50-64), 124 (67.4%) had post-procedural DWI lesions (median 4,IQR 2-10.5). Nerinetide treatment was associated with fewer iatrogenic infarcts but no overall significant clinical treatment effects. Patients with infarcts had lower Mini-Mental State Exam(MMSE) scores at 2-4 days (median 28 vs 29, adjusted-coefficient[acoef]: -1.11, 95%CI -1.88 to -0.34,p=0.005). Higher lesion counts were associated with worse day-1 NIHSS (aOR for NIHSS≥1:1.07, 1.02-1.12,p=0.009), day 2-4 mRS (adjusted common odds-ratio[aOR]: 1.05,1.01-1.09,p=0.005), and day 2-4 MMSE (acoef:-0.07,-0.13 to -0.003,p=0.040) scores. At 30-days, infarct number remained associated with worse mRS (aOR:1.04,1.01-1.07,p=0.016) and Hopkins Verbal Learning Test(HVLT) delayed-recall scores (acoef:-0.21,-0.39 to -0.03,p=0.020). Patients with infarcts trended towards lower 30-day Digit Symbol Substitution Test(DSST) scores (acoef:-3.73,-7.36 to -0.10,p=0.044). Higher lesion count was associated with worse composite outcome scores at both 1-4 days and 30-days (30-days acoef:-0.12,95%CI -0.21 to -0.03,p=0.008). Among those with infarcts, day-1 NIHSS and day 2-4 mRS correlated with 30-day NIHSS, DSST, HVLT, and mRS scores, whilst day 2-4 MMSE correlated with 30-day NIHSS and DSST scores (Spearman-Rho:0.47,p=0.001). Conclusions: Iatrogenic brain infarcts were associated with subtle differences in post-procedural (1-4 days) and 30-day outcomes on different measures in this middle-aged cohort, with earlier dysfunction correlating with later differences. Clinical trials registration: ClinicalTrials.gov, number NCT00728182.

Neurobiology of Recovery of Motor Function after Stroke: The Central Nervous System Biomarker Effects of Constraint-Induced Movement Therapy

Article

Full-text available

Jun 2020
Neural Plast

Recovery of motor function after stroke involves many biomarkers. This review attempts to identify the biomarker effects responsible for recovery of motor function following the use of Constraint-Induced Movement Therapy (CIMT) and discuss their implications for research and practice. From the studies reviewed, the biomarker effects identified include improved perfusion of motor areas and brain glucose metabolism; increased expression of proteins, namely, Brain-Derived Neurotrophic Factor (BDNF), Vascular Endothelial Growth Factor (VEGF), and Growth-Associated Protein 43 (GAP-43); and decreased level of Gamma-Aminobutyric Acid (GABA). Others include increased cortical activation, increased motor map size, and decreased interhemispheric inhibition of the ipsilesional hemisphere by the contralesional hemisphere. Interestingly, the biomarker effects correlated well with improved motor function. However, some of the biomarker effects have not yet been investigated in humans, and they require that CIMT starts early on poststroke. In addition, one study seems to suggest the combined use of CIMT with other rehabilitation techniques such as Transcortical Direct Stimulation (tDCs) in patients with chronic stroke to achieve the biomarker effects. Unfortunately, there are few studies in humans that implemented CIMT during early poststroke. Thus, it is important that more studies in humans are carried out to determine the biomarker effects of CIMT especially early on poststroke, when there is a greater opportunity for recovery. Furthermore, it should be noted that these effects are mainly in ischaemic stroke.

Ischemic Diffusion Lesion Reversal After Endovascular Treatment: Prevalence, Prognosis, and Predictors

Article

May 2019

Background and Purpose : Several studies have reported partial reversal of diffusion-weighted imaging (DWI) lesions after acute stroke reperfusion treatment. However, factors associated with DWI reversal have not yet been systematically investigated. We evaluated the factors associated with DWI reversal after endovascular treatment (EVT). Methods : We retrospectively analyzed consecutively encountered patients with acute ischemic stroke who underwent EVT at 3 comprehensive stroke centers in Korea from January 2011 to February 2016. Patients who received EVT within 24 hours of anterior circulation infarction and had both baseline and follow-up DWIs were included. DWI reversal was defined as a decrease in DWI volume from baseline to follow-up. We compared the characteristics and outcomes between patients with and without DWI reversal and assessed independent factors associated with DWI reversal. Results : Of 720 patients encountered during the time period, 404 patients (56.1%) met the study criteria, with 63 patients (15.5%) showing DWI reversal after EVT. The mean time interval between baseline and follow-up DWI was 4.7±2.4 days. Mean baseline DWI volumes of patients with and without DWI reversal were 30.1±36.7 versus 22.0±30.7 mL (P=0.106), and follow-up DWI volumes were 17.8±24.9 versus 68.7±77.5 mL (P<0.001). Patients with DWI reversal showed better functional outcomes at 3 months than those without DWI reversal (modified Rankin Scale [interquartile range], 1 [0–3] versus 2 [1–4]; P=0.001). In a multivariate analysis, complete reperfusion (odds ratio, 1.954; 95% CI, 1.063–3.582) and shorter time from baseline DWI to final reperfusion (odds ratio, 0.991; 95% CI, 0.983–0.998) were independently associated with DWI reversal. Conclusions : Complete reperfusion and shorter imaging time to recanalization were independently associated with DWI reversal among patients with acute ischemic stroke who received EVT.

Cerebral Ischemic Reperfusion Injury Following Recanalization of Large Vessel Occlusions

Article

Jul 2017
NEUROSURGERY

Although stroke has recently dropped to become the nation's fifth leading cause of mortality, it remains the top leading cause of morbidity and disability in the US. Recent advances in stroke treatment, including intravenous fibrinolysis and mechanical thromboembolectomy, allow treatment of a greater proportion of stroke patients than ever before. While intra-arterial fibrinolysis with recombinant tissue plasminogen is an effective for treatment of a broad range of acute ischemic strokes, endovascular mechanical thromboembolectomy procedures treat severe strokes due to large artery occlusions, often resistant to intravenous drug. Together, these procedures result in a greater proportion of revascularized stroke patients than ever before, up to 88% in 1 recent trial (EXTEND-IA). Subsequently, there is a growing need for neurointensivists to develop more effective strategies to manage stroke patients following successful reperfusion. Cerebral ischemic reperfusion injury (CIRI) is defined as deterioration of brain tissue suffered from ischemia that concomitantly reverses the benefits of re-establishing cerebral blood flow following mechanical or chemical therapies for acute ischemic stroke. Herein, we examine the pathophysiology of CIRI, imaging modalities, and potential neuroprotective strategies. Additionally, we sought to lay down a potential treatment approach for patients with CIRI following emergent endovascular recanalization for acute ischemic stroke.

A novel voxel-wise lesion segmentation technique on 3.0-T diffusion MRI of hyperacute focal cerebral ischemia at 1 h after permanent MCAO in rats

Article

Full-text available

Jun 2017

To assess hyperacute focal cerebral ischemia in rats on 3.0-Tesla diffusion-weighted imaging (DWI), we developed a novel voxel-wise lesion segmentation technique that overcomes intra- and inter-subject variation in apparent diffusion coefficient (ADC) distribution. Our novel technique involves the following: (1) intensity normalization including determination of the optimal type of region of interest (ROI) and its intra- and inter-subject validation, (2) verification of focal cerebral ischemic lesions at 1 h with gross and high-magnification light microscopy of hematoxylin-eosin (H&E) pathology, (3) voxel-wise segmentation on ADC with various thresholds, and (4) calculation of dice indices (DIs) to compare focal cerebral ischemic lesions at 1 h defined by ADC and matching H&E pathology. The best coefficient of variation was the mode of the left hemisphere after normalization using whole left hemispheric ROI, which showed lower intra- (2.54 ± 0.72%) and inter-subject (2.67 ± 0.70%) values than the original. Focal ischemic lesion at 1 h after middle cerebral artery occlusion (MCAO) was confirmed on both gross and microscopic H&E pathology. The 83 relative threshold of normalized ADC showed the highest mean DI (DI = 0.820 ± 0.075). We could evaluate hyperacute ischemic lesions at 1 h more reliably on 3-Tesla DWI in rat brains.

Magnetic resonance imaging-based cerebral tissue classification reveals distinct spatiotemporal patterns of changes after stroke in non-human primates

Article

Full-text available

Dec 2015
BMC NEUROSCI

Background: Spatial and temporal changes in brain tissue after acute ischemic stroke are still poorly understood. Aims of this study were three-fold: (1) to determine unique temporal magnetic resonance imaging (MRI) patterns at the acute, subacute and chronic stages after stroke in macaques by combining quantitative T2 and diffusion MRI indices into MRI 'tissue signatures', (2) to evaluate temporal differences in these signatures between transient (n = 2) and permanent (n = 2) middle cerebral artery occlusion, and (3) to correlate histopathology findings in the chronic stroke period to the acute and subacute MRI derived tissue signatures. Results: An improved iterative self-organizing data analysis algorithm was used to combine T2, apparent diffusion coefficient (ADC), and fractional anisotropy (FA) maps across seven successive timepoints (1, 2, 3, 24, 72, 144, 240 h) which revealed five temporal MRI signatures, that were different from the normal tissue pattern (P < 0.001). The distribution of signatures between brains with permanent and transient occlusions varied significantly between groups (P < 0.001). Qualitative comparisons with histopathology revealed that these signatures represented regions with different histopathology. Two signatures identified areas of progressive injury marked by severe necrosis and the presence of gitter cells. Another signature identified less severe but pronounced neuronal and axonal degeneration, while the other signatures depicted tissue remodeling with vascular proliferation and astrogliosis. Conclusion: These exploratory results demonstrate the potential of temporally and spatially combined voxel-based methods to generate tissue signatures that may correlate with distinct histopathological features. The identification of distinct ischemic MRI signatures associated with specific tissue fates may further aid in assessing and monitoring the efficacy of novel pharmaceutical treatments for stroke in a pre-clinical and clinical setting.

Regional Distribution of Selective Neuronal Loss and Microglial Activation across the MCA Territory after Transient Focal Ischemia: Quantitative versus Semiquantitative Systematic Immunohistochemical Assessment

Article

Oct 2014

Histopathologic assessment in transient middle cerebral artery occlusion (MCAo) rodent models generally lacks comprehensiveness and exposes to interobserver bias. Here we compared a novel quantitative assessment of regional infarction, selective neuronal loss (SNL) and microglial activation (MA) across the MCA territory to a previously published semiquantitative visual protocol. NeuN and OX42 immunohistochemistry was applied after either 15 or 45 minutes distal MCAo to maximize SNL and infarction, respectively. Survival times varied from 28 to 60 days to cover potential biases such as delayed tissue shrinkage. Damage was assessed using a template of 44 cytoarchitectonic regions of interest (ROIs) mapped onto a subset of digitized coronal sections spanning the MCA territory. For each ROI were obtained a semiquantitative visually determined index of histopathologic changes (method 1), and lpsilateral/contralesional ratios of remaining neurons and activated microglia cell counts (method 2). There was excellent agreement between the two methods for 28-day survival for both MCAo durations, whereas method 2 more sensitively detected subtle SNL and MA at 45 days and 60 days after 15-minute MCAo. Thus the visual method is accurate for usual degrees of ischemic damage, but absolute cell quantification is superior to detect subtle changes and should therefore be preferred in brief MCAo models, although requires optimal staining quality.Journal of Cerebral Blood Flow & Metabolism advance online publication, 29 October 2014; doi:10.1038/jcbfm.2014.181.

A longitudinal MRI and TSPO PET-based investigation of brain region-specific neuroprotection by diazepam versus midazolam following organophosphate-induced seizures

Article

Mar 2024
NEUROPHARMACOLOGY

How can imaging in acute ischemic stroke help us to understand tissue fate in the era of endovascular treatment and cerebroprotection?

Article

Jul 2022

Conventional laboratory housing increases morbidity and mortality in research rodents: results of a meta-analysis

Article

Full-text available

Jan 2022
BMC BIOL

Background Over 120 million mice and rats are used annually in research, conventionally housed in shoebox-sized cages that restrict natural behaviours (e.g. nesting and burrowing). This can reduce physical fitness, impair thermoregulation and reduce welfare (e.g. inducing abnormal stereotypic behaviours). In humans, chronic stress has biological costs, increasing disease risks and potentially shortening life. Using a pre-registered protocol (https://atrium.lib.uoguelph.ca/xmlui/handle/10214/17955), this meta-analysis therefore tested the hypothesis that, compared to rodents in ‘enriched’ housing that better meets their needs, conventional housing increases stress-related morbidity and all-cause mortality. Results Comprehensive searches (via Ovid, CABI, Web of Science, Proquest and SCOPUS on May 24 2020) yielded 10,094 publications. Screening for inclusion criteria (published in English, using mice or rats and providing ‘enrichments’ in long-term housing) yielded 214 studies (within 165 articles, using 6495 animals: 59.1% mice; 68.2% male; 31.8% isolation-housed), and data on all-cause mortality plus five experimentally induced stress-sensitive diseases: anxiety, cancer, cardiovascular disease, depression and stroke. The Systematic Review Center for Laboratory animal Experimentation (SYRCLE) tool assessed individual studies’ risks of bias. Random-effects meta-analyses supported the hypothesis: conventional housing significantly exacerbated disease severity with medium to large effect sizes: cancer (SMD = 0.71, 95% CI = 0.54–0.88); cardiovascular disease (SMD = 0.72, 95% CI = 0.35–1.09); stroke (SMD = 0.87, 95% CI = 0.59–1.15); signs of anxiety (SMD = 0.91, 95% CI = 0.56–1.25); signs of depression (SMD = 1.24, 95% CI = 0.98–1.49). It also increased mortality rates (hazard ratio = 1.48, 95% CI = 1.25–1.74; relative median survival = 0.91, 95% CI = 0.89–0.94). Meta-regressions indicated that such housing effects were ubiquitous across species and sexes, but could not identify the most impactful improvements to conventional housing. Data variability (assessed via coefficient of variation) was also not increased by ‘enriched’ housing. Conclusions Conventional housing appears sufficiently distressing to compromise rodent health, raising ethical concerns. Results also add to previous work to show that research rodents are typically CRAMPED (cold, rotund, abnormal, male-biased, poorly surviving, enclosed and distressed), raising questions about the validity and generalisability of the data they generate. This research was funded by NSERC, Canada.

Brain Protection in the Endo-Management of Proximal Aortic Aneurysms

Article

Full-text available

Jul 2020

Neurological brain injury (NBI) remains the most feared complication following thoracic endovascular aortic repair (TEVAR), and can manifest as clinically overt stroke and/or more covert injury, detected only on explicit neuropsychological testing. Microembolic signals (MES) detected on transcranial Doppler (TCD) monitoring of the cerebral arteries during TEVAR and the high prevalence and incidence of new ischaemic infarcts on diffusion-weighted magnetic resonance imaging (DW-MRI) suggests procedure-related solid and gaseous cerebral microembolisation to be an important cause of NBI. Any intervention that can reduce the embolic burden during TEVAR may, therefore, help mitigate the risk of stroke and the covert impact of ischaemic infarcts to the function of the brain. This perspective article provides an understanding of the mechanism of stroke and reviews the available evidence regarding potential neuroprotective strategies that target high-risk procedural steps of TEVAR to reduce periprocedural cerebral embolisation.

The contribution of acute infarcts to cerebral small vessel disease progression

Article

Full-text available

Jul 2019

Objective: To determine the contribution of acute infarcts, evidenced by diffusion-weighted imaging positive (DWI+) lesions to progression of white matter hyperintensities (WMH) and other cerebral small vessel disease (SVD) markers. Methods: We performed 10 monthly 3 T MRIs in 54 elderly individuals with SVD. MRI included high-resolution multi-shell DWI, and 3D FLAIR, T1 and SWI. We determined DWI+ lesion evolution, WMH progression rate (mL/month), and number of incident lacunes and microbleeds, and calculated for each marker the proportion of progression explained by DWI+ lesions. Results: We identified 39 DWI+ lesions on 21/472 DWI scans in 9/54 subjects. Of the 36 DWI+ lesions with follow-up MRI, two evolved into WMH, four into a lacune (three of which with cavity < 3 mm), three into a microbleed, and 27 were not detectable on follow-up. WMH volume increased at a median rate of 0.027 (0.005-0.073) mL/month, but was not significantly higher in subjects with DWI+ lesions compared to those without (p = 0.195). Of the two DWI+ lesions evolving into WMH on follow-up, one explained 23% of the total WMH volume increase in one subject, whereas WMH regressed in the other subject. DWI+ lesions preceded 4/5 incident lacunes, and 3/10 incident microbleeds. Interpretation: DWI+ lesions explain only a small proportion of the total WMH progression. Hence, WMH progression seems to be mostly driven by factors other than acute infarcts. DWI+ lesions explain the majority of incident lacunes and small cavities, and almost a third of incident microbleeds, confirming that WMH, lacunes, and microbleeds, although heterogeneous on MRI, can have a common initial appearance on MRI. This article is protected by copyright. All rights reserved.

Early changes in transient adenosine during cerebral ischemia and reperfusion injury

Article

Full-text available

May 2018
PLOS ONE

Adenosine is an important neuromodulator in the central nervous system, and tissue adenosine levels increase during ischemic events, attenuating excitotoxic neuronal injury. Recently, our lab developed an electrochemical fast-scan cyclic voltammetry (FSCV) method that identified rapid, spontaneous changes in adenosine concentrations that last only about 3 seconds. Here, we investigated the effects of cerebral ischemia and reperfusion on the concentration and frequency of transient adenosine release in the caudate-putamen. In anesthetized rats, data were collected for four hours: two hours of normoxia, 30 min of cerebral ischemia induced by bilateral common carotid artery occlusion, and 90 min of reperfusion. Transient adenosine release was increased during the cerebral ischemia period and remained elevated during reperfusion. The total number of adenosine transients increased by 52% during cerebral ischemia and reperfusion compared to normoxia. The concentration of adenosine per event did not increase but the cumulative adenosine concentration during cerebral ischemia and reperfusion increased by 53% because of the higher frequency of events. Further, we evaluated the role of A2A antagonist, SCH442416, a putative neuroprotective agent to affect adenosine transients. SCH442416 significantly decreased the transient frequency during cerebral ischemia-reperfusion by 27% and the cumulative concentration by 31%. Our results demonstrate that this mode of rapid adenosine release increases during early cerebral ischemia-reperfusion injury. Rapid adenosine release could provide fast, local neuromodulation and neuroprotection during cerebral ischemia.

Combination of Emricasan with Ponatinib Synergistically Reduces Ischemia/Reperfusion Injury in Rat Brain Through Simultaneous Prevention of Apoptosis and Necroptosis

Article

Full-text available

Aug 2018

Apoptosis and receptor-interacting protein kinase 1/3(RIPK1/3)-mediated necroptosis contribute to the cerebral ischemia/reperfusion (I/R) injury. Emricasan is an inhibitor of caspases in clinical trials for liver diseases while ponatinib could be a potential inhibitor for RIPK1/3. This study aims to investigate the effect of emricasan and/or ponatinib on cerebral I/R injury and the underlying mechanisms. Firstly, we evaluated the status of apoptosis and necroposis in a rat model of cerebral I/R under different conditions, which showed noticeable apoptosis and necroptosis under condition of 2-h ischemia and 24-h reperfusion; next, the preventive or therapeutic effect of emricasan or ponatinib on cerebral I/R injury was tested. Administration of emricasan or ponatinib either before or after ischemia could decrease the neurological deficit score and infarct volume; finally, the combined therapeutic effect of emricasan with ponatinib on I/R injury was examined. Combined application of emricasan and ponatinib could further decrease the I/R injury compared to single application. Emricasan decreased the activities of capase-8/-3 in the I/R-treated brain but not the protein levels of necroptosis-relevant proteins: RIPK1, RIPK3, and mixed lineage kinase domain-like (MLKL), whereas ponatinib suppressed the expressions of these proteins but not the activities of capase-8/-3. Combination of emricasan with ponatinib could suppress both capase-8/-3 and necroptosis-relevant proteins. Based on these observations, we conclude that combination of emricasan with ponatinib could synergistically reduce I/R injury in rat brain through simultaneous prevention of apoptosis and necroptosis. Our findings might lay a basis on extension of the clinical indications for emricasan and ponatinib in treating ischemic stroke.

Animal models of ischaemic stroke and characterisation of the ischaemic penumbra

Article

Sep 2017
NEUROPHARMACOLOGY

Over the past forty years, animal models of focal cerebral ischaemia have allowed us to identify the critical cerebral blood flow thresholds responsible for irreversible cell death, electrical failure, inhibition of protein synthesis, energy depletion and thereby the lifespan of the potentially salvageable penumbra. They have allowed us to understand the intricate biochemical and molecular mechanisms within the 'ischaemic cascade' that initiate cell death in the first minutes, hours and days following stroke. Models of permanent, transient middle cerebral artery occlusion and embolic stroke have been developed each with advantages and limitations when trying to model the complex heterogeneous nature of stroke in humans. Yet despite these advances in understanding the pathophysiological mechanisms of stroke-induced cell death with numerous targets identified and drugs tested, a lack of translation to the clinic has hampered pre-clinical stroke research. With recent positive clinical trials of endovascular thrombectomy in acute ischaemic stroke the stroke community has been reinvigorated, opening up the potential for future translation of adjunctive treatments that can be given alongside thrombectomy/thrombolysis. This review discusses the major animal models of focal cerebral ischaemia highlighting their advantages and limitations. Acute imaging is crucial in longitudinal pre-clinical stroke studies in order to identify the influence of acute therapies on tissue salvage over time. Therefore, the methods of identifying potentially salvageable ischaemic penumbra are discussed.

Imaging of cerebral ischemic edema and neuronal death

Article

Full-text available

Jun 2017
NEURORADIOLOGY

PurposeIn acute cerebral ischemia, the assessment of irreversible injury is crucial for treatment decisions and the patient’s prognosis. There is still uncertainty how imaging can safely differentiate reversible from irreversible ischemic brain tissue in the acute phase of stroke. Methods We have searched PubMed and Google Scholar for experimental and clinical papers describing the pathology and pathophysiology of cerebral ischemia under controlled conditions. ResultsWithin the first 6 h of stroke onset, ischemic cell injury is subtle and hard to recognize under the microscope. Functional impairment is obvious, but can be induced by ischemic blood flow allowing recovery with flow restoration. The critical cerebral blood flow (CBF) threshold for irreversible injury is ~15 ml/100 g × min. Below this threshold, ischemic brain tissue takes up water in case of any residual capillary flow (ionic edema). Because tissue water content is linearly related to X-ray attenuation, computed tomography (CT) can detect and measure ionic edema and, thus, determine ischemic brain infarction. In contrast, diffusion-weighted magnetic resonance imaging (DWI) detects cytotoxic edema that develops at higher thresholds of ischemic CBF and is thus highly sensitive for milder levels of brain ischemia, but not specific for irreversible brain tissue injury. ConclusionCT and MRI are complimentary in the detection of ischemic stroke pathology and are valuable for treatment decisions.

Proposed Standardized Neurological Endpoints for Cardiovascular Clinical Trials

Article

Feb 2017

Surgical and catheter-based cardiovascular procedures and adjunctive pharmacology have an inherent risk of neurological complications. The current diversity of neurological endpoint definitions and ascertainment methods in clinical trials has led to uncertainties in the neurological risk attributable to cardiovascular procedures and inconsistent evaluation of therapies intended to prevent or mitigate neurological injury. Benefit-risk assessment of such procedures should be on the basis of an evaluation of well-defined neurological outcomes that are ascertained with consistent methods and capture the full spectrum of neurovascular injury and its clinical effect. The Neurologic Academic Research Consortium is an international collaboration intended to establish consensus on the definition, classification, and assessment of neurological endpoints applicable to clinical trials of a broad range of cardiovascular interventions. Systematic application of the proposed definitions and assessments will improve our ability to evaluate the risks of cardiovascular procedures and the safety and effectiveness of preventive therapies. (J Am Coll Cardiol 2017;▪:▪-▪) © 2017 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Brain Emboli After Left Ventricular Endocardial Ablation

Article

Jan 2017

Background: -Catheter ablation for ventricular tachycardia (VT) and premature ventricular complexes (PVCs) is common. Catheter ablation of atrial fibrillation is associated with a risk of cerebral emboli attributed to cardioversions and numerous ablation lesions in the low-flow left atrium, but cerebral embolic risk in ventricular ablation has not been evaluated. Methods: -We enrolled 18 consecutive patients meeting study criteria scheduled for VT or PVC ablation over a 9-month period. Patients undergoing left ventricular (LV) ablation were compared to a control group of those undergoing right ventricular (RV) ablation only. Patients were excluded if they had implantable cardiac defibrillators or permanent pacemakers. Radiofrequency energy was used for ablation in all cases and heparin was administered with goal activated clotting times of 300-400 seconds for all LV procedures. Pre- and post-procedural brain magnetic resonance imaging (MRI) was performed on each patient within a week of the ablation procedure. Embolic infarcts were defined as new foci of reduced diffusion and high signal intensity on fluid-attenuated inversion recovery brain MRI within a vascular distribution. Results: -The mean age was 58 years, half were men, half had a history of hypertension, and the majority had no known vascular disease or heart failure. LV ablation was performed in 12 patients (VT, n=2; PVC, n=10) and exclusively RV ablation in 6 patients (VT, n=1; PVC, n=5). Seven patients (58%) undergoing LV ablation experienced a total of 16 cerebral emboli, compared with zero patients undergoing RV ablation (p = 0.04). Seven of 11 patients (63%) undergoing a retrograde approach to the LV developed at least one new brain lesion. Conclusions: -More than half of patients undergoing routine LV ablation procedures (predominately PVC ablations) experienced new brain emboli after the procedure. Future research is critical to understanding the long-term consequences of these lesions and to determine optimal strategies to avoid them.

Preserved Collateral Blood Flow in the Endovascular M2CAO Model Allows for Clinically Relevant Profiling of Injury Progression in Acute Ischemic Stroke

Article

Full-text available

Jan 2017
PLOS ONE

Interventional treatment regimens have increased the demand for accurate understanding of the progression of injury in acute ischemic stroke. However, conventional animal models severely inhibit collateral blood flow and mimic the malignant infarction profile not suitable for treatment. The aim of this study was to provide a clinically relevant profile of the emergence and course of ischemic injury in cases suitable for acute intervention, and was achieved by employing a M2 occlusion model (M2CAO) that more accurately simulates middle cerebral artery (MCA) occlusion in humans. Twenty-five Sprague-Dawley rats were subjected to Short (90 min), Intermediate (180 min) or Extended (600 min) transient M2CAO and examined longitudinally with interleaved diffusion-, T2- and arterial spin labeling perfusion-weighted magnetic resonance imaging before and after reperfusion. We identified a rapid emergence of cytotoxic edema within tissue regions undergoing infarction, progressing in several distinct phases in the form of subsequent moderation and then reversal at 230 min (p < 0.0001). We identified also the early emergence of vasogenic edema, which increased consistently before and after reperfusion (p < 0.0001). The perfusion of the penumbra correlated more strongly to the perfusion of adjacent tissue regions than did the perfusion of regions undergoing infarction (p = 0.0088). This was interpreted as an effect of preserved collateral blood flow during M2CAO. Accordingly, we observed only limited recruitment of penumbra regions to the infarction core. However, a gradual increase in infarction size was still occurring as late as 10 hours after M2CAO. Our results indicate that patients suffering MCA branch occlusion stand to benefit from interventional therapy for an extended time period after the emergence of ischemic injury.

Change of Apparent Diffusion Coefficient Immediately after Recanalization through Intra-Arterial Revascularization Therapy in Acute Ischemic Stroke

Article

Full-text available

Jan 2016

Intra-arterial revascularization therapy (IART) for acute ischemic stroke has become increasingly popular recently. However, early change in apparent diffusion coefficient (ADC) values after full recanalization in human stroke has not received much attention. The aim of this study was to evaluate ADC changes immediately after interventional full-recanalization in patients with acute ischemic stroke.

Mapping the dynamics of brain perfusion using functional ultrasound in a rat model of transient middle cerebral artery occlusion

Article

Full-text available

Dec 2015

Following middle cerebral artery occlusion, tissue outcome ranges from normal to infarcted depending on depth and duration of hypoperfusion as well as occurrence and efficiency of reperfusion. However, the precise time course of these changes in relation to tissue and behavioral outcome remains unsettled. To address these issues, a three-dimensional wide field-of-view and real-time quantitative functional imaging technique able to map perfusion in the rodent brain would be desirable. Here, we applied functional ultrasound imaging, a novel approach to map relative cerebral blood volume without contrast agent, in a rat model of brief proximal transient middle cerebral artery occlusion to assess perfusion in penetrating arterioles and venules acutely and over six days thanks to a thinned-skull preparation. Functional ultrasound imaging efficiently mapped the acute changes in relative cerebral blood volume during occlusion and following reperfusion with high spatial resolution (100 µm), notably documenting marked focal decreases during occlusion, and was able to chart the fine dynamics of tissue reperfusion (rate: one frame/5 s) in the individual rat. No behavioral and only mild post-mortem immunofluorescence changes were observed. Our study suggests functional ultrasound is a particularly well-adapted imaging technique to study cerebral perfusion in acute experimental stroke longitudinally from the hyper-acute up to the chronic stage in the same subject.

Methylene Blue Ameliorates Ischemia/Reperfusion-Induced Cerebral Edema: An MRI and Transmission Electron Microscope Study

Article

Jan 2016
Acta Neurochir

The neuroprotective effect of methylene blue (MB) has been identified against various brain disorders, including ischemic stroke. In the present study, we evaluated the effects of MB on postischemic brain edema using magnetic resonance imaging (MRI) and transmission electron microscopy (TEM). Adult male rats were subjected to transient focal cerebral ischemia induced by 1 h middle cerebral artery occlusion (MCAO), followed by reperfusion. MB was infused intravenously immediately after reperfusion (3 mg/kg) and again at 3 h post-occlusion (1.5 mg/kg). Normal saline was administered as vehicle control. Sequential MRIs, including apparent diffusion coefficient (ADC) and T2-weighted imaging (T2WI), were obtained at 0.5, 2.5, and 48 h after the onset of stroke. Separated groups of animals were sacrificed at 2.5 and 48 h after stroke for ultrastructural analysis by TEM. In addition, final lesion volumes were analyzed by triphenyltetrazolium chloride (TTC) staining at 48 h after stroke. Ischemic stroke induced ADC lesion volume at 0.5 h during MCAOs that were temporally recovered at 1.5 h after reperfusion. No significant difference in ADC-defined lesion was observed between vehicle and MB treatment groups. At 48 h after stroke, MB significantly reduced ADC lesion and T2WI lesion volume and attenuated cerebral swelling. Consistently, MB treatment significantly decreased TTC-defined lesion volume at 48 h after stroke. TEM revealed remarkable swollen astrocytes, astrocytic perivascular end-feet, and concurrent shrunken neurons in the penumbra at 2.5 and 48 h after MCAO. MB treatment attenuated astrocyte swelling, the perivascular astrocytic foot process, and endothelium and also alleviated neuron degeneration. This study demonstrated that MB could decrease postischemic brain edema and provided additional evidence that future clinical investigation of MB for the treatment of ischemic stroke is warrented.

Case report of a young stroke patient showing interim normalization of the MRI diffusion-weighted imaging lesion

Article

Full-text available

Aug 2015
BMC Med Imag

In acute ischemic stroke, diffusion weighted imaging (DWI) shows hyperintensities and is considered to indicate irreversibly damaged tissue. We present the case of a young stroke patient with unusual variability in the development of signal intensities within the same vessel territory. A 35-year-old patient presented with symptoms of global aphasia and hypesthesia of the left hand. MRI demonstrated a scattered lesion in the MCA territory. After rtPA therapy the patient received further MRI examination, three times on day 1, and once on day 2, 3, 5 and 43. The posterior part of the lesion showed the usual pattern with increasing DWI hyperintensity and decreased ADC, as well as delayed FLAIR positivity. However, the anterior part of the lesion, which was clearly visible in the first examination completely normalized on the first day and only reappeared on day 2. This was accompanied by a normalization of the ADC as well as an even further delayed FLAIR positivity. We showed that interim normalization of DWI and ADC in the acute phase can not only be found in rodent models of stroke, but also in humans. We propose that DWI lesion development might be more variable during the first 24 h after stroke than previously assumed.

Apparent diffusion coefficient mapping predicts mortality and outcome in rats with intracerebral haemodynamic disturbance: potential role of intraoperative diffusion and perfusion weighted magnetic resonance imaging to detect cerebral ischaemia

Article

Oct 2002
BRIT J ANAESTH

S Ishikawa

Background. Usefulness and ability of diffusion and perfusion weighted magnetic resonance images (DWI and PWI) to detect intracerebral haemodynamic disturbance have not been fully evaluated. Methods. After the right common carotid artery had been ligated, rats were exsanguinated to maintain a mean arterial pressure of 35, 42, or 50 mm Hg (n=6, each group). Apparent diffusion coefficient (ADC) maps were calculated from DWIs and lesion volume (area) was defined based on ADC values (ADC lesion volume (area)). Results. ADC lesion volume during exsanguination in the 35 mm Hg group (417 (111) mm³, P<0.01) was significantly larger than in the 42 mm Hg group (87 (84) mm³) and 50 mm Hg group (42 (58) mm³). The low relative cerebral blood flow area, calculated from PWI, was significantly larger during exsanguination in the 35 mm Hg group than in the other groups. ADC lesion volume in the six rats that died within 3 days of the MRI study was significantly larger (median 421 mm³, range 205–476 mm³, P<0.005) than in the 12 rats that survived for 3 days (median 26 mm³, range 3–517 mm³). Rats with an ADC lesion area over 14 mm² on the coronal slice including the caudate putamen during exsanguination died within 3 days or revealed a more severe histopathological outcome than those that survived for 3 days. Conclusions. Incomplete cerebral ischaemia created by the combination of common carotid artery occlusion and exsanguination could be detected by DWI and PWI both qualitatively and quantitatively. The size of the lesion on ADC mapping was found to correlate with mortality and outcome. Br J Anaesth 2002; 89: 605–13

Focal middle cerebral artery ischemia in rats via a transfemoral approach using a custom designed microwire

Article

May 2015
J Neurointerv Surg

The aim of this study was to develop a reliable and repeatable method of inducing focal middle cerebral artery occlusion (MCAo) in rats without ligation of the external carotid artery (ECA), while reducing the risk of subarachnoid hemorrhage. We prototyped microwires with different diameters (0.0120 inch, 0.0115 inch, 0.0110 inch), materials, and construction methods (coil-on-core, extruded polymer jacket-on-core). Under fluoroscopic guidance and using femoral artery access, the microwires were navigated into the internal carotid artery of male Wistar rats (n=50, weight 376±64 g) to induce MCAo for 1 or 2 h. We performed neurological assessments at baseline, and at 3, 24, 72, and 168 h after MCAo. MRI measurements were performed on a 9.4 T scanner at 1 and 7 days post-injury. The 0.0115 inch microwire with polymer jacket-on-core provided the most successful outcome. At 1 and 7 days post-injury, we observed similar infarction volumes for 1 and 2 h MCAo in the MRI study. Infarcted lesion volumes in both MCAo groups were significantly reduced at 7 days compared with 1 day post-injury. The trend in longitudinal changes for the scores of different neurological assessments was confirmed to be significant after the injury, but both groups showed a similar trend of neurological deficits over the course of the study. We have developed a reliable and repeatable MCAo method in rats, allowing for precise occlusion of the MCA under direct fluoroscopic visualization without alteration of the cerebral hemodynamics associated with ECA ligation. The custom designed microwire can also be sized for targeted focal ischemia in larger animals. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

The quest for a better insight into physiology of fluids and barriers of the brain: The exemplary career of Joseph D. Fenstermacher

Article

Full-text available

Jan 2015

In June 2014 Dr. Joseph D. Fenstermacher celebrated his 80th birthday, which was honored by the symposium held in New London, NH, USA. This review discusses Fenstermacher's contribution to the field of fluids and barriers of the CNS. Specifically, his fundamental work on diffusion of molecules within the brain extracellular space and the research on properties of the blood-brain barrier in health and disease are described. Fenstermacher's early research on cerebrospinal fluid dynamics and the regulation of cerebral blood flow is also reviewed, followed by the discussion of his more recent work involving the use of magnetic resonance imaging.

Therapeutic efficacy of brain imaging in acute ischemic stroke patients

Article

Nov 2014
J NEURORADIOLOGY

This article reviews main pathological findings in ischemic stroke patients as imaged with CT, CTA, MRI, and MRA and discusses its clinical effectiveness on different levels: technical, diagnostic accuracy, impact on diagnosis and treatment decisions affecting patient clinical outcome. It emphasizes the importance of detecting ischemic brain tissue damage (infarction) early during a time period when reperfusion therapy may be beneficial and provides evidence that brain tissue hypoattenuation as displayed by non-enhanced CT represents net water uptake (ionic edema) that is highly accurate in defining brain tissue that will not recover with reperfusion whereas MRI is highly sensitive in detecting patterns of ischemic brain tissue even in stages that allow functional recovery. Copyright © 2014. Published by Elsevier Masson SAS.

Fate of Diffusion Restricted Lesions in Acute Intracerebral Hemorrhage

Article

Full-text available

Aug 2014
PLOS ONE

Background Diffusion-restricted lesions on diffusion-weighted imaging (DWI) are detected in patients with intracerebral hemorrhage (ICH). In this study, we aimed to determine the fate of DWI lesions in ICH patients and whether the presence of DWI lesions is associated with functional outcome in patients with ICH. Methods This prospective study enrolled 153 patients with acute ICH. Baseline MRI scans were performed within 2 weeks after ICH to detect DWI lesions and imaging markers for small vessel disease (SVD). Follow-up MRI scans were performed at 3 months after ICH to assess the fate of the DWI lesions. We analyzed the associations between the characteristics of DWI lesions with clinical features and functional outcome. Results Seventeen of the 153 patients (11.1%) had a total of 25 DWI lesions. Factors associated with DWI lesions were high initial systolic and mean arterial blood pressure (MAP) at the emergency room, additional lowering of MAP within 24 hours, and the presence of white matter hyperintensity and cerebral microbleeds. Thirteen of the 25 DWI lesions (52%) were not visible on follow-up T2-weighted or fluid-attenuated inversion recovery images and were associated with high apparent diffusion coefficient value and a sharper decease in MAP. The regression of DWI lesions was associated with good functional outcome. Conclusions More than half of the DWI lesions in the ICH patients did not transition to visible, long-term infarction. Only if the DWI lesion finally transitioned to final infarction was a poor functional outcome predicted. A DWI lesion may be regarded as an ischemic change of SVD and does not always indicate certain cerebral infarction or permanent tissue injury.

Early Diffusion-Weighted Imaging Reversal After Endovascular Reperfusion Is Typically Transient in Patients Imaged 3 to 6 Hours After Onset

Article

Feb 2014
STROKE

The aim of this study was to assess the frequency and extent of early diffusion-weighted imaging (DWI) lesion reversal after endovascular therapy and to determine whether early reversal is sustained or transient. MRI with DWI perfusion imaging was performed before (DWI 1) and within 12 hours after (DWI 2) endovascular treatment; follow-up MRI was obtained on day 5. Both DWIs were coregistered to follow-up MRI. Early DWI reversal was defined as the volume of the DWI 1 lesion that was not superimposed on the DWI 2 lesion. Permanent reversal was the volume of the DWI 1 lesion not superimposed on the day 5 infarct volume. Associations between early DWI reversal and clinical outcomes in patients with and without reperfusion were assessed. A total of 110 patients had technically adequate DWI before endovascular therapy (performed median [interquartile range], 4.5 [2.8-6.2] hours after onset); 60 were eligible for this study. Thirty-two percent had early DWI reversal >10 mL; 17% had sustained reversal. The median volume of permanent reversal at 5 days was 3 mL (interquartile range, 1.7-7.0). Only 2 patients (3%) had a final infarct volume that was smaller than their baseline DWI lesion. Early DWI reversal was not an independent predictor of clinical outcome and was not associated with early reperfusion. Early DWI reversal occurred in about one third of patients after endovascular therapy; however, reversal was often transient and was not associated with a significant volume of tissue salvage or favorable clinical outcome.

Imaging Oxygen Metabolism in Acute Stroke Using MRI

Article

Full-text available

Mar 2014

The ability to image the ischemic penumbra during hyper-acute stroke promises to identify patients who may benefit from treatment intervention beyond population-defined therapeutic time windows. MR blood oxygenation level dependent (BOLD) contrast imaging has been explored in ischemic stroke. This review provides an overview of several BOLD-based methods, including susceptibility weighted imaging (SWI), R2, R2*, R2', R2* under oxygen challenge, MR_OEF and MROMI approaches to assess cerebral oxygen metabolism in ischemic stroke. We will review the underlying pathophysiological basis of the imaging approaches, followed by a brief introduction of BOLD contrast. Finally, we will discuss the applications of the BOLD approaches in patients with ischemic stroke. BOLD-based methods hold promise for imaging tissue oxygenation during acute ischemia. Further technical refinement and validation studies in stroke patients against positron emission tomography (PET) measurements are needed.

Pro-Inflammatory Mediators and Apoptosis Correlate to rt-PA Response in a Novel Mouse Model of Thromboembolic Stroke

Article

Full-text available

Jan 2014
PLOS ONE

A recent study suggests that patients with persistent occlusion of the middle cerebral artery (MCA) following treatment with recombinant tissue plasminogen activator (rt-PA) have better outcomes than patients with MCA occlusion not receiving rt-PA. We performed a study to elucidate possible mechanisms of this finding in a new model of thromboembolic stroke closely mimicking human pathophysiology. Thromboembolic stroke was induced by local injection of thrombin directly into the right MCA of C57 black/6J mice. Rt-PA was administered 20 and 40 min after clot formation. The efficiency of rt-PA to induce thrombolysis was measured by laser Doppler. After 24 h, all animals were euthanized and interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), matrix metalloproteinase (MMP)-9, Caspase-3, hsp 32 and hsp 70 protein levels were investigated by immunofluorescence. Presence of hemorrhage was verified and infarct volume was measured using histology. Thrombin injection resulted in clot formation giving rise to cortical brain infarction. Early rt-PA treatment starting at 20 min after the clot formation resulted in 100% recanalization. However, rt-PA-induced thrombolysis dissolved the clot in only 38% of the animals when administered 40 min after clot formation. Protein levels of IL-6, TNF-α, MMP-9, Caspase-3, hsp 32 and hsp 70 were increased after MCAO, whereas treatment with rt-PA attenuated the expressions of inflammatory markers in those animals where the thrombolysis was successful. In addition, the infarct size was significantly reduced with rt-PA treatment compared to non-treated MCAO, regardless of whether MCA thrombolysis was successful. The present study demonstrates a clear correlation of the protein expression of inflammatory mediators, apoptosis and stress genes with the recanalization data after rt-PA treatment. In this model rt-PA treatment decreases the infarct size regardless of whether vessel recanalization is successful.

Pronostic factors on MRI in patients with acute ischemic stroke

Thesis

Nov 2018

Yu Xie

MRI plays an important role in evaluating ischemic stroke and determining the treatment strategies. Diffusion weighted imaging and perfusion weighted imaging are two essential sequences in ischemic stroke assessment. The principal objective of this work was to study the predictive role of MRI in ischemic stroke, including the role of MRI-derived parameters in tissue viability prediction; the relationship of the ischemic lesional volume and the functional outcome and mechanical thrombectomy efficacy; and the impact of the pretreatment ischemic location on functional outcome after mechanical thrombectomy. Our results suggested that apparent diffusion coefficient and relative cerebral blood flow were potential candidates to predict tissue viability; pretreatment lesional volume was an independent predictor for functional outcome; the clinical benefit of adding mechanical thrombectomy to thrombolysis decreased with the increase of lesional volume; however, patients with large lesional volume could still benefit from reperfusion treatment; the pretreatment ischemic location provided important prognostic information for functional outcome. The overall results of the thesis provided a better understanding of the role of MRI in acute ischemic stroke assessment, especially in patients treated with mechanical thrombectomy. Our work provided new perspective in clinical application of MRI and suggested future research of ischemic stroke imaging

Reversible parenchymal ischemic injury on fetal brain MRI following fetoscopic laser coagulation—Implication on parental counseling

Article

Full-text available

Aug 2020

We present a case of reversible extensive ischemic injury seen on fetal-brain MRI in a fetus following laser coagulation performed for treatment of severe twin-twin transfusion syndrome twin-twin transfusion syndrome. A 32-year-old pregnant mother presented with twin-twin transfusion syndrome. Following fetoscopic laser coagulation, intrauterine fetal death of the donor fetus was diagnosed. On fetal-brain MRI, multiple areas of restricted diffusion were noted, consistent with acute infarctions. Nevertheless, follow-up MRI showed only subtle parenchymal injury, also confirmed on postnatal brain MRI. Our case illustrates that ischemic injury, as depicted on diffusion-weighted imaging, might be reversible, possibly with reperfusion before irreversible insult follows. Two to 3 weeks follow-up fetal MRI might provide additional information on the extent of irreversible injury in cases of restricted diffusion seen on initial fetal-brain MRI and might assist in parental counseling regarding long-term sequela.

Multiparametric classification of sub‐acute ischemic stroke recovery with ultrafast diffusion, 23 Na, and MPIO‐labeled stem cell MRI at 21.1 T

Article

Dec 2019

MRI leverages multiple modes of contrast to characterize stroke. High‐magnetic‐field systems enhance the performance of these MRI measurements. Previously, we have demonstrated that individually sodium and stem cell tracking metrics are enhanced at ultrahigh field in a rat model of stroke, and we have developed robust single‐scan diffusion‐weighted imaging approaches that utilize spatiotemporal encoding (SPEN) of the apparent diffusion coefficient (ADC) for these challenging field strengths. Here, we performed a multiparametric study of middle cerebral artery occlusion (MCAO) biomarker evolution focusing on comparison of these MRI biomarkers for stroke assessment during sub‐acute recovery in rat MCAO models at 21.1 T. T2‐weighted MRI was used as the benchmark for identification of the ischemic lesion over the course of the study. The number of MPIO‐induced voids measured by gradient‐recalled echo, the SPEN measurement of ADC, and 23Na MRI values were determined in the ischemic area and contralateral hemisphere, and relative performances for stroke classification were compared by receiver operator characteristic analysis. These measurements were associated with unique time‐dependent trajectories during stroke recovery that changed the sensitivity and specificity for stroke monitoring during its evolution. Advantages and limitations of these contrasts, and the use of ultrahigh field for multiparametric stroke assessment, are discussed. MRI parameters of sub‐acute stroke recovery were evaluated at ultrahigh field (21.1 T). Trajectories of apparent diffusion coefficient, tracking of MPIO‐labeled stem cells, and sodium levels were evaluated, and found to exhibit differing ROC performance for stroke classification. Jointly addressing anatomical, microstructural, cellular, and metabolic level information with ultrahigh‐field MRI can improve classification of stroke and recovery in vivo.

Imaging After Thrombolysis and Thrombectomy: Rationale, Modalities and Management Implications

Article

Full-text available

Aug 2019
CURR NEUROL NEUROSCI

Purpose of Review Urgent reperfusion treatment with intravenous thrombolysis or mechanical thrombectomy reduces disability after ischaemic stroke. Imaging plays an important role in identifying patients who benefit, particularly in extended time windows. However, the role of post-treatment neuroimaging is less well established. We review recent advances in neuroimaging after reperfusion treatment and provide a practical guide to the options and management implications. Recent Findings Post-treatment imaging is critical to identify patients with reperfusion-related haemorrhage and oedema requiring intervention. It also can guide the timing and intensity of antithrombotic medication. The degree of reperfusion on post-thrombectomy angiography and infarct volume and topography using CT or MRI carry important prognostic significance. Perfusion-weighted MRI and permeability analysis may help detect persistent perfusion abnormalities post-treatment and predict haemorrhagic complications. Summary Post-treatment neuroimaging provides clinically relevant information to identify complications, assess prognosis and perform quality assurance after acute ischaemic stroke. Recent advances in neuroimaging represent a potential avenue to explore post-reperfusion pathophysiology and uncover therapeutic targets for secondary ischaemic and haemorrhagic injury.

Association between Striatal Brain Iron Deposition, Microbleeds and Cognition 1 Year After a Minor Ischaemic Stroke

Article

Full-text available

Mar 2019
INT J MOL SCI

Brain iron deposits (IDs) are inversely associated with cognitive function in community-dwelling older people, but their association with cognition after ischemic stroke, and whether that differs from microbleeds, is unknown. We quantified basal ganglia IDs (BGID) and microbleeds (BMBs) semi-automatically on brain magnetic resonance images from patients with minor stroke (NIHSS < 7), at presentation and 12 months after stroke. We administered the National Adult Reading Test (NART, estimates premorbid or peak adult cognition) and the Revised Addenbrooke’s Cognitive Examination (ACE-R; current cognition) at 1 and 12 months after stroke. We adjusted analyses for baseline cognition, age, gender, white matter hyperintensity (WMH) volume and vascular risk factors. In 200 patients, mean age 65 years, striatal IDs and BMBs volumes did not change over the 12 months. Baseline BGID volumes correlated positively with NART scores at both times (ρ = 0.19, p < 0.01). Baseline and follow-up BGID volumes correlated positively with age (ρ = 0.248, p < 0.001 and ρ = 0.271, p < 0.001 respectively), but only baseline (and not follow-up) BMB volume correlated with age (ρ = 0.129, p < 0.05). Both smoking and baseline WMH burden predicted verbal fluency and visuospatial abilities scores (B = −1.13, p < 0.02 and B = −0.22, p = 0.001 respectively) at 12 months after stroke. BGIDs and BMBs are associated differently with cognition post-stroke; studies of imaging and post-stroke cognition should adjust for premorbid cognition. The positive correlation of BGID with NART may reflect the lower premorbid cognition in patients with stroke at younger vs older ages.

Untersuchung der Okklusionsrate und der thromboembolischen Komplikationen nach endovaskulärer Behandlung von nicht rupturierten intrakraniellen Aneurysmen

Thesis

Jan 2007

Panagiotis Papanagiotou

Proposed Standardized Neurological Endpoints for Cardiovascular Clinical Trials

Article

Feb 2017

The Ischemic Penumbra and the Therapeutic Time Window

Chapter

Jan 2001

Marc Fisher

Two key concepts for developing effective therapy for acute stroke are 1) what ischémic tissue is the therapeutic target; and 2) when is this tissue likely to respond? The portion of the ischemic zone potentially responsive to therapy is called the ischemic penumbra and the time during which it might be reversibly injured is the therapeutic time window. These intertwined concepts of a potentially reversible ischemic region and when it might respond to a variety of therapeutic interventions are the foundation of current ongoing efforts to develop effective acute stroke therapies. Potentially salvageable ischemic tissue is the presumed therapeutic target for both thrombolytic and neuroprotective stroke therapy, and the time period of potentially successful treatment is a key issue for patient recruitment. Consideration of both concepts is clearly important for researchers and clinicians interested in focal brain ischemia. Major advances have occurred during the past several years.

The dynamic change of MR imaging in acute ischemic stroke with tPA therapy

Article

Full-text available

Jan 2017

We investigated the dynamic change of MR imaging in acute ischemic stroke with the tPA therapy in our hospital where 3.0T-MRI can support for 24 hours. The clinical data for 62 patients who received intravenous tPA for acute ischemic stroke and MR imaging before, during, and after the tPA of between April 2012 and December 2015. We investigated the change of MR imaging and clinical observation. Nineteen patients (24%) achieved early recanalization more than TICI 2A during tPA or TICI 2B within 8 hours of symptom onset. The DWI lesion reduction (DWI LR) was observed in 6 (10%) patients. In 30 minutes after the tPA, 63% of early recanalization group achieved TICI 2B, and DWI LR was observed in some cases. Early recanalization was related to the DWI LR, dramatic improvement of symptom and good outcome. NIHSS (22 in the LR group, and 16 in the non-LR group) and ASPECTS+W (7 in the LR group, and 8 in the non-LR group) were significantly different in early recanalization group. DWI lesion which disappeared in early phase might regrow between subacute and clonic phase. MR imaging changed dynamically in a short term after the tPA therapy. Early recanalization provides the dramatic improvement of symptom and good outcome, and reduces the DWI lesion of the relatively wide infarction range.

Diagnostic performance of CT cerebral blood volume colour maps for evaluation of acute infarcts; comparison with diffusion-weighted MRI within 12hours of major stroke onset

Article

Feb 2017
J NEURORADIOLOGY

Background and purpose: Recent developments in treatment of ischemic stroke increased importance of defining limits of ischemic insult by imaging. Some studies postulated that CTP is a promising technique, which can discriminate between ischemic core and penumbra. In this study, we sought to evaluate diagnostic performance of CTP-CBV colour maps, regarded as a marker of acute infarct; in comparison with DWI. Materials and methods: We retrospectively analyzed 48 patients with CTA proved major ischemic stroke within 12hours of onset, they had DWI and CTP exams within 1hour of each other, regardless of order. DWI sizes were calculated. Sensitivity, specificity, PPV and NPV of CBV colour maps for identification of acute infarcts were calculated. ROC curve was constructed. Results: CBV colour maps missed a lot of small infarcts that were identified by DWI with an overall diagnostic accuracy of (62.5%) and low sensitivity (38.5%) for patients whom DWI size<70mL. Area under curve was 0.79. DWI size was an only predictor of abnormal CBV colour maps (P=0.005). Conclusions: Assuming direct equivalence of DWI and CBV-based core might be unrealistic for individual patients in clinical practice. CBV colour maps are highly specific for acute infarcts, but with lack of sufficient sensitivity; particularly for small sized infarcts.

Diffusion-weighted imaging uncovers likely sources of processing-speed deficits in schizophrenia

Article

Nov 2016

Significance Advanced, non-Gaussian diffusion-weighted imaging (DWI) measurements that probe white matter microstructure across a range of diffusion contrasts were sensitive to diagnosis-specific abnormalities in schizophrenia and independently predicted patient–control differences in processing speed. Two orthogonal statistical factors extracted from DWI measurements explain most of diagnosis-related differences in processing speed. Moreover, DWI measurements explained a similar degree of variance in processing speed in patients and controls separately and in siblings of patients. This link remains contiguous across the diagnostic boundary and was not driven by subject selection or antipsychotic medication. The non-Gaussian diffusion white matter metrics are promising surrogate imaging markers for modeling cognitive deficits and perhaps, guiding treatment development.

The Ischemic Penumbra and Cell Survival

Chapter

Nov 2015

Patrick Lyden

For centuries, physicians believed the brain would tolerate no more than a few minutes of ischemia without suffering permanent cell death. In the 1980s, a series of investigations proved that irreparable damage affects only a portion of the brain tissue so quickly after focal ischemia. Cells in the surrounding region, referred to as the 'ischemic penumbra,' may remain viable for several hours. The elucidation of the penumbra concept-especially the notion that brain regions tolerated prolonged ischemia without permanent death-inspired thoughts about thrombolysis as a possible treatment for stroke. Vascular occlusion results in an immediate drop in cerebral blood flow, cerebral perfusion, and cerebral metabolism within the territory supplied by the occluded artery. The classic model of the penumbra includes a core region where blood flow is too low to allow cell survival, and a surrounding zone where marginal flow allows brain to survive but not function. Cells in the penumbra metabolize slowly, called "idling" to suggest that they are salvageable. In the core, cells die rapidly (within minutes) whereas cells in the penumbra may survive for up to several hours. Restoration of blood flow to this area within an hour or so may salvage the 'viable' cells and diminish the degree of neurological deficits. If reperfusion begins early, penumbral tissue may survive. Neuroprotection targets the penumbra; agents that block the sequence of metabolic events triggered by ischemia might prolong cell survival in the penumbra until such a time as flow is restored. To date, no neuroprotectant has yet entered widespread clinical use.

Effects of a TAFI-Inhibitor combined with sub-optimal dose of rtPA, evaluated with multimodal MRI, in a murine thromboembolic model of stroke

Article

Dec 2013

Anne Durand

The benefit of recombinant tissue plasminogen activator (rtPA) treatment in stroke is well known with serious side effects requiring the evaluation of alternative strategies. Injection of thrombin in the middle cerebral artery of mice has been proposed as a new model of thromboembolic stroke. In the first study, we used multiparametric Magnetic Resonance Imaging (MRI), performed immediately after thrombin injection, to document occlusion and area at risk in this model. Despite similar MCA occlusion and marked hypoperfusion, half of animals showed a cortical lesion on DWI, while the other half demonstrated no or very limited lesion. Therefore, MRI measurement of basal lesion size is required to use this animal model in therapeutic studies. The second study compared efficacy between TAFI inhibitor alone and TAFI inhibitor in combination with low-dose rtPA. In conclusion, we showed that the combination of TAFI-I with low-dose rtPA is not as effective as the standard dose of rtPA, with a positive trend, while TAFI inhibition alone is not effective at all. The present thromboembolic model is of particular interest in assessing strategies rtPA association to improve thrombolysis, especially when coupled with longitudinal MRI assessment

Einfluss von Cortical Spreading Depolarization auf eine verzögerte Infarktprogression bei Patienten mit malignem Schlaganfall

Thesis

Apr 2015

Alexandra Pinczolits

Der Schlaganfall steht hinter den Herz- und Tumor-Erkrankungen an dritter Stelle aller Todesursachen. Der wichtigste Faktor für die Vermeidung dauerhafter Invalidität und die Wiederherstellung maximaler Lebensqualität ist die Verhinderung von sekundären Komplikationen. Dabei stellt die Infarktprogression eine der schwerwiegendsten Komplikationen dar. Im Rahmen dieser Arbeit konnte bei insgesamt 45 Patienten mit einem malignen Schlaganfall mittels serieller MRT-Aufnahmen bestimmt werden, ob eine Infarktprogression vorlag. Ein Schwerpunkt der Arbeit war es, die hämodynamische Antwort und die zeitliche und räumliche Ausbreitung von Spreading Depolarizationen (CSD) im Periinfarktgewebe von Patienten mit malignem Schlaganfall zu untersuchen. In dieser Studie konnte zum ersten Mal die zeitliche und räumliche Ausbreitung von CSDs und deren hämodynamische Kopplung am humanen Kortex gezeigt werden. In einer zweiten Substudie wurden mit Hilfe der zerebralen Mikrodialyse die Konzentrationen von Glutamat, Glukose, Laktat und Pyruvat im Periinfarktgewebe bestimmt. Damit sollte im Besonderen geklärt werden, ob es Unterschiede in den Konzentrationen bei Patienten mit Infarktprogression zu Patienten ohne Infarktprogression gibt. Zusammenfassend war ein bemerkenswerter Anteil von verzögerter Infarktprogression nach Dekompression bei Patienten mit malignem Schlaganfall assoziiert mit veränderten biochemischen Markern innerhalb der Periinfarktregion. Des Weiteren wurde untersucht, inwiefern CSDs mit einer veränderten Konzentration von Glutamat, Glukose, Laktat und Pyruvat einhergeht. Hierzu wurde eine Korrelation zwischen CSDs und den Mikrodialysekonzentrationen von Glutamat, Glukose, Laktat und Pyruvat erstellt.

Untersuchung der Okklusionsrate und der thromboembolischen Komplikationen nach endovaskulärer Behandlung von nicht rupturierten intrakraniellen Aneurysmen

Article

Apr 2008

Panagiotis Papanagiotou

Present status and future challenges of electroencephalography- and magnetic resonance imaging-based monitoring in preclinical models of focal cerebral ischemia

Article

Jan 2014

Reversal of Perfusion and Diffusion Abnormalities After Intravenous Thrombolysis for a Lacunar Infarction

Article

Apr 2003
J NEUROIMAGING

Perfusion and diffusion magnetic resonance imaging (MRI) have been used to guide therapy in patients with large vessel occlusions. In an analogous fashion, the authors used perfusion and diffusion MRI to demonstrate a perfusion deficit and a matching diffusion lesion in a patient with lacunar infarct. Following thrombolytic therapy, the authors observed a reversal of the perfusion deficit, the diffusion lesion, and clinical recovery. This case suggests that perfusion and diffusion MRI may be informative in patients with lacunar infarction who are candidates for thrombolysis.

MRI diffusion mapping of reversible and irreversible ischemic injury in focal brain ischemia

Article

Full-text available

Sep 1994

The reduction of the apparent diffusion coefficient (ADC) of water shortly after a focal ischemic insult is thought to reflect intracellular water accumulation (cytotoxic edema) related to high-energy metabolism failure and loss of ion homeostasis. We attempted to clarify whether varying ranges of ADC measurements in ischemic brain tissue can be used to differentiate between reversible and irreversible ischemic lesions before reperfusion in a temporary ischemia model. We induced 45 minutes of temporary ischemia in 12 rats using the middle cerebral artery suture occlusion method. Regional changes of ADC values were serially measured in seven regions of interest in each hemisphere and evaluated by delta ADC, defined as the difference between ADC value in an ischemic region and that in a contralateral homologous region. We acquired dynamic contrast-enhanced perfusion images 2 minutes before and after reperfusion to document reduced perfusion and its restoration. We confirmed the infarct area by 2,3,5-triphenyltetrazolium chloride staining 24 hours after occlusion and correlated this with the MRI studies. Recovery of initially reduced ADC values occurred only in ischemic regions where delta ADC values were not below -0.25 x 10(-5) cm2/sec. Although the extent of infarction at postmortem examination varied in regions with moderately decreased prereperfusion ADC values, more than 70% of regions of interest with slight declines of prereperfusion ADC values exhibited no infarction. ADC values progressively decreased after reperfusion in regions that initially had severely decreased prereperfusion ADC values, and postmortem examination always demonstrated infarction in such regions.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitative Measurement of Regional Blood-Flow with Gadolinium Diethylenetriaminepentaacetate Bolus Track Nmr Imaging in Cerebral Infarcts in Rats - Validation with the Iodo[C-14]Antipyrine Technique

Article

Full-text available

Apr 1995

NMR bolus track measurements were correlated with autoradiographically determined regional cerebral blood flow (rCBF). The NMR method is based on bolus infusion of the contrast agent gadolinium diethylenetriaminepentaacetate and high-speed T*2-sensitive NMR imaging. The first pass of the contrast agent through the image plane causes a transient decrease of the signal intensity. This time course of the signal intensity is transformed into relative concentrations of the contrast agent in each pixel. The mean transit time and relative blood flow and volume are calculated from such indicator dilution curves. We investigated whether this NMR technique correctly expresses the relative rCBF. The relative blood flow data, calculated from NMR bolus track experiments, and the absolute values of iodo[14C]antipyrine autoradiography were compared. A linear relationship was observed, indicating the proportionality of the transient NMR signal change with CBF. Excellent interindividual reproducibility of calibration constants is observed (r = 0.963). For a given NMR protocol, bolus track measurements calibrated with autoradiography after the experiment allow determination of absolute values for rCBF and regional blood volume.

Diffusion-Weighted Magnetic Resonance Imaging of Acute Focal Cerebral Ischemia: Comparison of Signal Intensity with Changes in Brain Water and Na + ,K+-ATPase Activity

Article

Full-text available

Mar 1994

Diffusion-weighted magnetic resonance (MR) images from rats during acute cerebral ischemia induced by middle cerebral artery occlusion were analyzed for correspondence with changes in brain water, cation concentrations, and Na+,K(+)-ATPase activity measured in vitro after 30 or 60 min of ischemia. In the ischemic hemisphere, signal intensity was increased at 30 min (p < 0.05 vs contralateral hemisphere) and further increased at 60 min. Na+,K(+)-ATPase activity was 34% lower in ischemic cortex and 40% lower in ischemic basal ganglia after 30 min (p < 0.05), but water content and Na+ and K+ concentrations were not significantly different between hemispheres. After 60 min, water content and Na+ concentration were increased, and both Na+,K(+)-ATPase activity and K+ concentration were decreased in the ischemic hemisphere (p < 0.05). These findings are consistent with the hypothesis that the early onset of signal hyperintensity in diffusion-weighted MR images may reflect cellular edema associated with impaired membrane pump function. Early in vivo detection and localization of potentially reversible ischemic cerebral edema may have important research and clinical applications.

In vivo mapping of brain benzodiazepine receptor changes by positron emission tomography after focal ischemia in anesthetized baboon

Article

Full-text available

Jan 1994

Recent reports have shown an increase in specific binding (in vitro) of [3H]PK 11195 to peripheral-type benzodiazepine receptors in both experimental animals and humans, reflecting a glial/macrophagic reaction within and around focal ischemic insults. We have evaluated by positron emission tomography the time course of changes in brain uptake in vivo of 11C-labeled PK 11195 and flumazenil (an antagonist of central benzodiazepine receptors) as indirect and direct markers of neuronal loss, respectively, after focal cerebral ischemia. Ten anesthetized baboons were submitted to sequential positron emission tomography studies between day 1 and day 91 after unilateral middle cerebral artery occlusion. The studies consisted of successive assessments, in the same positron emission tomography session, of [11C]PK 11195, [11C]flumazenil, cerebral blood flow, and oxygen consumption; late computed tomographic scans were obtained to map the approximate contours of infarction and to define a concentric peri-infarct area. We found a significant time-dependent increase in [11C]PK 11195 uptake in the peri-infarcted area, maximum at 20 to 40 days after occlusion. In contrast, there was a time- and perfusion-independent significant decrease in [11C]flumazenil uptake in the infarcted area, stable from day 2 onward, and already present in one baboon at day 1. Challenge studies with saturating doses of cold ligands confirmed that these changes represented alterations in specific binding. [11C]Flumazenil uptake was not affected in hypometabolic (but apparently noninfarcted, ie, deafferented) cortical areas. The delayed and apparently transient increases in [11C]PK 11195 specific uptake in vivo presumably represent glial/macrophage reaction; the marked depression in [11C]flumazenil specific binding, which appears selective for synaptic damage, is both precocious and sustained and thus may be better suited for the early assessment of ischemic damage in humans.

Diffusion-weighted MR Imaging: Diagnostic Accuracy in Patients Imaged within 6 Hours of Stroke Symptom Onset

Article

Full-text available

Jan 1999

To evaluate the diagnostic accuracy of diffusion-weighted magnetic resonance (MR) imaging performed within 6 hours of the onset of stroke symptoms. The authors reviewed the patient records and images from all patients hospitalized in a 10-month period in whom diffusion-weighted imaging was performed within 6 hours of the onset of strokelike symptoms (n = 22). Analyses included comparison of the initial interpretation of the diffusion-weighted images with the final clinical diagnosis; blinded reviews of computed tomographic (CT) scans and conventional and diffusion-weighted images; and determination of lesion contrast-to-noise ratios (CNRs). Diffusion-weighted images indicated stroke in 14 patients, all of whom had a final diagnosis of acute stroke. Diffusion-weighted images were negative in eight patients, all of whom had a final clinical diagnosis other than stroke (100% sensitivity, 100% specificity, chi 2 = 23.00, P < .0001). Blinded reviews yielded 100% sensitivity and 86% specificity for diffusion-weighted MR imaging (chi 2 = 15.43, P < .0005); 18% sensitivity and 100% specificity for conventional MR imaging (chi 2 = 2.85, P > .2); and 45% sensitivity and 100% specificity for CT (chi 2 = 4.40, P > .10). Lesion percentage CNRs were 77% for diffusion-weighted imaging, 5.5% for CT, 9.8% for T2-weighted MR imaging, and 3.1% for proton-density-weighted MR imaging (P < .002 for diffusion-weighted imaging vs others). Diffusion-weighted MR imaging is highly accurate for diagnosing stroke within 6 hours of symptom onset and is superior to CT and conventional MR imaging.

Experimental studies of ischemic brain edema. I. A new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischemic area

Article

Jan 1986

Magnetic resonance imaging of acute stroke (vol 18, pg 593, 1998)

Article

Oct 1998

Comparison of diffusion- and T2-weighted MRI for the early detection of cerebral ischemia and reperfusion in rats

Article

Diffusion-weighted imaging studies of cerebral ischemia in gerbils. Potential relevance to energy failure

Article

Nov 1992

Background and purpose: Diffusion-weighted magnetic resonance imaging has been shown to be particularly suited to the study of the acute phase of cerebral ischemia in animal models. The studies reported in this paper were undertaken to determine whether this technique is sensitive to the known ischemic thresholds for cerebral tissue energy failure and disturbance of membrane ion gradients. Methods: Diffusion-weighted images of the gerbil brain were acquired under two sets of experimental conditions: as a function of cerebral blood flow after controlled graded occlusion of the common carotid arteries (partial ischemia), as a function of time following complete bilateral carotid artery occlusion (severe global ischemia), and on deocclusion after 60 minutes of ischemia. Results: During partial cerebral ischemia, the diffusion-weighted images remained unchanged until the cerebral blood flow was reduced to 15-20 ml.100 g-1.min-1 and below, when image intensity increased as the cerebral blood flow was lowered further. This is similar to the critical flow threshold for maintenance of tissue high-energy metabolites and ion homeostasis. After the onset of severe global cerebral ischemia, diffusion-weighted image intensity increased gradually after a delay of approximately 2.5 minutes, consistent with complete loss of tissue adenosine triphosphate and with the time course of increase in extracellular potassium. This hyperintensity decreased on deocclusion following 60 minutes of ischemia. Conclusions: The data suggest that diffusion-weighted imaging is sensitive to the disruption of tissue energy metabolism or a consequence of this disruption. This raises the possibility of imaging energy failure noninvasively. In humans, this could have potential in visualizing brain regions where energy metabolism is impaired, particularly during the acute phase following stroke.

High Temporal Resolution Diffusion MRI of Global Cerebral Ischemia and Reperfusion

Article

Sep 1996

Although brain ischemia has been extensively studied using diffusion-weighted magnetic resonance imaging, most studies performed so far have not had adequate time resolution to follow the temporal changes in the water apparent diffusion coefficient (ADC) in hyperacute ischemia. Using diffusion echo planar imaging, we obtained ADC maps (calculated from measurements made with 8 b-values) with a time resolution of 43 s in a feline model of global brain ischemia and reperfusion. Different protocols were performed: 10-min hypoperfusion, 10- and 22-min ischemia followed by reperfusion, and cardiac arrest. ADC values were obtained from white matter of the internal capsule and from the thalamus. Cortical gray matter measurements were not deemed reliable due to the close proximity of CSF in the cortical sulci. Following occlusion, the ADC declined in the thalamus to <2 SD of its normal baseline value within 1.5–2.5 min. This decay was exponential with a time constant (τ ± SD) of 6.0 ± 2.6 min; no further decrease in the ADC was observed 10 min following ischemia. Following reperfusion, in animals that showed ADC recovery, the ADC began increasing immediately, returning to its preischemic value in ~15 min. No significant ADC changes were observed during hypoperfusion. Following cardiac arrest, the decay of ADC was more rapid in the thalamus (τ = 2.6 ± 0.6 min) than in white matter (τ = 6.6 ± 1.8 min). We observed that the ADC at 40 min after cardiac arrest was similar to the ADC at 10 min after ischemia. Given that all animals subjected to 10-min ischemic episodes showed ADC recovery with reperfusion, doubt is cast on whether it is possible to define a threshold value of the ADC below which brain tissue is irreversibly damaged. Finally, despite variability in the time constants of the ADC decay induced by ischemia, the ADC values at 10 min were very similar in all the animals. This suggests that when blood flow is diminished sufficiently to induce an ADC reduction, differences in perfusion affect the rapidity of the decrease but not the final asymptotic value reached.Keywords: Brain; Diffusion-weighted imaging; Echo planar imaging; Ischemia; Magnetic resonance imaging; Metabolism; White matter

Pitfalls in MR measurement of tissue blood flow with intravascular tracers: Which mean transit time?

Article

Apr 1993
MAGN RESON MED

Measuring tissue blood flow with NMR imaging of intravascular tracers is more difficult than measurements of tissue blood volume. One major obstacle to the application of the Central Volume Principle is the direct measurement of the mean transit time. In this note, we demonstrate that mean transit time (MTT), which relates tissue blood volume to blood flow via the Central Volume Principle, is not the first moment of the concentration-time curve for MR or CT imaging of purely intravascular tracers. However, while first moment methods cannot be used by themselves to determine absolute flow, we show that transit curves may provide a useful relative measure of flow, for example, by considering ratios of the first moments.

Single-shot diffusion imaging at 2.0 Tesla

Article

Feb 1990

A single-shot echo-planar diffusion imaging sequence (IVIM-EPI: intra-voxel incoherent motion echo-planar imaging) is presented, which is immune from the motion artifacts which may seriously impair images obtained using other diffusion imaging sequences. For a static water phantom, the measured value of diffusion constant (D = 2.30 × 10−9 m2 s−1 at T = 298 K) shows excellent agreement with that obtained using a multipulse spin-echo technique and with literature values. Single-shot diffusion imaging can now be used reliably to make dynamic time-course studies with excellent time resolution.

Dynamics of Cerebral Tissue Injury and Perfusion After Temporary Hypoxia-Ischemia in the Rat: Evidence for Region-Specific Sensitivity and Delayed Damage

Article

Mar 1998

Selective regional sensitivity and delayed damage in cerebral ischemia provide opportunities for directed and late therapy for stroke. Our aim was to characterize the spatial and temporal profile of ischemia-induced changes in cerebral perfusion and tissue status, with the use of noninvasive MRI techniques, to gain more insight in region-specific vulnerability and delayed damage. Rats underwent 20 minutes of unilateral cerebral hypoxia-ischemia (HI). We performed combined repetitive quantitative diffusion-weighted, T2-weighted, and dynamic susceptibility contrast-enhanced MRI from before HI to 5 hours after HI. Data were correlated with parallel blood oxygenation level-dependent MRI and laser-Doppler flowmetry. Finally, MRI and histology were done 24 and 72 hours after HI. Severe hypoperfusion during HI caused acute reductions of the apparent diffusion coefficient (ADC) of tissue water in the ipsilateral hemisphere. Reperfusion resulted in dynamic perfusion alterations that varied spatially. The ADC recovered completely within 1 hour in the hippocampus (from 0.68 +/- 0.07 to 0.83 +/- 0.09 x 10[-3] mm2/s), cortex (from 0.56 +/- 0.06 to 0.77 +/- 0.07 x 10[-3] mm2/s), and caudate putamen (from 0.58 +/- 0.06 to 0.75 +/- 0.06 x 10[-3] mm2/s) but only partially or not at all in the thalamus (from 0.65 +/- 0.07 to 0.68 +/- 0.12 x 10[-3] mm2/s) and substantia nigra (from 0.80 +/- 0.08 to 0.76 +/- 0.10 x 10[-3] mm2/s). Secondary ADC reductions, accompanied by significant T2 elevations and histological damage, were observed after 24 hours. Initial and secondary ADC decreases were observed invariably in the hippocampus, cortex, and caudate putamen and in approximately 70% of the animals in the thalamus and substantia nigra. Region-specific responses and delayed ischemic damage after transient HI were demonstrated by MRI. Acute reperfusion-induced normalization of ADCs appeared to poorly predict ultimate tissue recovery since secondary, irreversible damage developed eventually.

Temporal evolution of ischemic injury evaluated with diffusion-, perfusion-, and T2-weighted MRI

Article

Mar 2000

Objective: Ischemic lesions seen on diffusion-weighted imaging (DWI) are reversible if reperfusion is performed within minutes after the onset of ischemia. This study was designed to determine whether acute reversibility of DWI abnormalities is transient following brief temporary focal brain ischemia and to characterize the temporal evolution of in vivo ischemic lesions. Methods: Eight rats were subjected to 30 minutes of temporary middle cerebral artery occlusion and underwent diffusion-, perfusion-, and T2-weighted MRI during occlusion; immediately after reperfusion; 30, 60, and 90 minutes after reperfusion; and 12, 24, 48, and 72 hours after reperfusion. Average apparent diffusion coefficient (ADCav) values and the cerebral blood flow index (CBFi) ratio were calculated in both the lateral caudoputamen and overlying cortex at each time point. The size of the in vivo ischemic abnormalities was calculated from the ADCav and the T2 maps. Postmortem triphenyltetrazolium chloride (TTC) staining was used to verify ischemic injury. Results: Both the CBFi ratio and ADCav values declined significantly in the two regions during occlusion. The CBFi ratio recovered immediately after reperfusion and remained unchanged over 72 hours. However, ADCav values returned to normal at 60 to 90 minutes and secondarily decreased at 12 hours after reperfusion as compared with those in the contralateral hemisphere. The extent of the in vivo ischemic lesions maximized at 48 hours and was highly correlated with TTC-derived lesion size. Conclusions: Acute recovery of initial ADCav-defined lesions after reperfusion is transient, and secondary ADCav-defined lesions develop in a slow and delayed fashion.

Diffusion-weighted magnetic resonance imaging: Rapid and quantitative detection of focal brain ischemia

Article

Feb 1992

We examined serial changes of diffusion- (DWI) and T2-weighted (T2WI) magnetic resonance images 30 minutes to 3 hours after intraluminal suture occlusion of the middle cerebral artery (MCA) in eight rats and after sham occlusion in four. We correlated the abnormal areas on DWI and T2WI with postmortem areas of infarction determined by 2,3,5-triphenyltetrazolium chloride (TTC), 24 hours after the operation. The 30-minute DWI in each MCA-occluded rat demonstrated increased signal intensity in the ipsilateral MCA territory, while T2WI showed no changes. At 3 hours, the ipsilateral DWI signal intensity increased further and the area of abnormality slightly increased. In some animals, the 3-hour T2WI disclosed an area of hyperintensity significantly smaller than that seen on the 30-minute DWI. TTC staining demonstrated an extensive MCA infarction in all rats with permanent MCA occlusion, confirmed by hematoxylin and eosin staining. The percent infarcted area of coronal brain sections, as determined by TTC staining, correlated significantly with areas on similar DWI sections at both 30 minutes and 3 hours. Sham-occluded control animals did not display any changes on DWI, T2WI, or TTC staining. The present study suggests that DWI is a very sensitive modality for detecting early ischemic brain injury, being highly correlated with post-mortem area of infarction, and may be useful to assess pharmacologic intervention.

Mechanism of Detection of Acute Cerebral Ischemia in Rats by Diffusion-Weighted Magnetic Resonance Spectroscopy

Article

Jun 1992

The aim of this study was to measure apparent diffusion coefficients in rat brain tissue exposed to ouabain, glutamate, and N-methyl-D-aspartate and to compare them with apparent diffusion coefficients found in acute cerebral ischemia. The apparent diffusion coefficient was measured using magnetic resonance microscopy in four groups of Sprague-Dawley rats after occlusion of the right middle cerebral artery and ipsilateral common carotid artery (n = 7), after ouabain exposure (n = 6), during glutamate exposure (n = 7), or during N-methyl-D-aspartate exposure (n = 3). Ouabain, glutamate, and N-methyl-D-aspartate were applied via an intracerebrally implanted microdialysis membrane. Three hours after the induction of focal cerebral ischemia, a 33% reduction in the apparent diffusion coefficient was observed in the right dorsolateral corpus striatum and olfactory cortex. After ouabain exposure, reductions in the apparent diffusion coefficient were observed within a 1,500-microns radius of the microdialysis membrane. Quantitative analysis revealed that apparent diffusion coefficient values in ischemic and ouabain-exposed tissue fell within the same range. Glutamate and N-methyl-D-aspartate reduced the brain tissue apparent diffusion coefficient by 35% and 40%, respectively. On the basis of these findings, we conclude that ischemia-induced apparent diffusion coefficient reductions are likely caused by a shift of extracellular to intracellular water.

Reversible Focal Ischemic Injury Demonstrated by Diffusion-Weighted Magnetic Resonance Imaging in Rats

Article

Oct 1992

Diffusion-weighted magnetic resonance imaging (DWI) can quantitatively display focal brain abnormalities within minutes after the onset of ischemia. We performed the present study to determine the effects of 1 and 2 hours of temporary ischemia on DWI. We examined DWI and T2-weighted magnetic resonance images (T2WI) during and after 1 and 2 hours of temporary middle cerebral artery occlusion in rats (n = 10 for each group). In a subgroup of four animals from each group, we employed perfusion magnetic resonance imaging to monitor cerebral perfusion. Neurological outcome and infarct size after survival for 24 hours were compared between the groups and correlated with DWI and T2WI studies. Perfusion studies qualitatively documented hypoperfusion and reperfusion during and after temporary occlusion. Lesion size on DWI during reperfusion was significantly less than that during ischemia for 1 (55% decline, p less than 0.02) but not 2 hours of occlusion. The DWI signal intensity ratio (intensity compared with that in the contralateral homologous area) just before withdrawal of the occluder was significantly less in regions where the hyperintensity disappeared after withdrawal than in regions with persistent hyperintensity (p less than 0.002). The T2WI studies revealed few or no abnormalities, except after 2 hours of occlusion. The neurological outcome was significantly better in the 1-hour than in the 2-hour group (p less than 0.05). Postmortem infarct volume was significantly smaller in the 1-hour group than in the 2-hour group (p less than 0.05). The postwithdrawal DWI accurately predicted infarct size (R = 0.96, p less than 0.0001). The present study indicates that DWI can rapidly display not only irreversible but also reversible ischemic brain damage and enhances the importance of DWI as a diagnostic modality for stroke.

Detection with echo-planar MR imaging of transit of susceptibility contrast medium in a rat model of regional brain ischemia

Article

May 1991

Gradient-refocused echo-planar magnetic resonance (MR) images (TE = 18 msec) were acquired in rats during bolus injection of iron oxide particles, and the first pass of the contrast agent through the brain was monitored. In control rats, contrast agent (0.1 mmol/kg iron) produced significant signal-intensity (SI) reduction over the right hemisphere and similar declines over the left. SI loss occurred first in the cortex and basal ganglia and later in the periventricular regions, along the midline, and in the thalamic zone. Sequential volume-localized proton spectra acquired during transit of 0.02 mmol/kg iron showed substantial reduction in SI, slight asymmetric broadening, and no change in chemical shift of the water resonance. In rats with unilateral occlusion of the middle cerebral artery, peak reduction in ischemic brain SI was to 70% +/- 9% of control, while normal brain SI was reduced to 18% +/- 2% (P less than .01), allowing distinction of the ischemic regions. The presence and location of injury were confirmed with diffusion-weighted imaging and postmortem vital staining. These results demonstrate abnormal transit profiles in a rat model of regional brain ischemia. Evaluation of dynamic contrast delivery patterns may provide unique information in early brain ischemia.

Diffusion-weighted MR imaging of acute stroke: Correlation with T2-weighted and magnetic susceptibility-enhanced MR imaging in cats

Article

Jun 1990

We evaluated the temporal and anatomic relationships between changes in diffusion-weighted MR image signal intensity, induced by unilateral occlusion of the middle cerebral artery in cats, and tissue perfusion deficits observed in the same animals on T2-weighted MR images after administration of a nonionic intravascular T2 shortening agent. Diffusion-weighted images obtained with strong diffusion-sensitizing gradient strengths (5.6 gauss/cm, corresponding to gradient attenuation factor, b, values of 1413 sec/mm2) displayed increased signal intensity in the ischemic middle cerebral artery territory less than 1 hr after occlusion, whereas T2-weighted images without contrast usually failed to detect injury for 2-3 hr after stroke. After contrast administration (0.5-1.0 mmol/kg by Dy-DTPA-BMA, IV), however, T2-weighted images revealed perfusion deficits (relative hyperintensity) within 1 hr after middle cerebral artery occlusion that corresponded closely to the anatomic regions of ischemic injury shown on diffusion-weighted MR images. Close correlations were also found between early increases in diffusion-weighted MR image signal intensity and disrupted phosphorus-31 and proton metabolite levels evaluated with surface coil MR spectroscopy, as well as with postmortem histopathology. These data indicate that diffusion-weighted MR images more accurately reflect early-onset pathophysiologic changes induced by acute cerebral ischemia than do T2-weighted spin-echo images.

Incomplete cerebral infarction--focal incomplete ischemic tissue necrosis not leading to emollision

Article

Jul 1982

N A Lassen

Ischemic Delayed Neuronal Death : A Mitochondrial Hypothesis

Article

Sep 1995

A brief period of global brain ischemia causes cell death in hippocampal CA1 pyramidal neurons days after reperfusion in rodents and humans. Other neurons are much less vulnerable. This phenomenon is commonly referred to as delayed neuronal death, but the cause has not been fully understood although many mechanisms have been proposed. Hippocampal CA1 neuronal death usually occurs 3 to 4 days after an initial ischemic insult. Such a delay is essential for the mechanism of this type of cell death. Previous hypotheses have not well explained the reason for the delay and the exact mechanism of the cell death, but a disturbance of mitochondrial gene expression could be a possibility. Reductions of mitochondrial RNA level and the activity of a mitochondrial protein, encoded partly by mitochondrial DNA, occurred exclusively in CA1 neurons at the early stage of reperfusion and were aggravated over time. In contrast, the activity of a nuclear DNA-encoded mitochondrial enzyme and the level of mitochondrial DNA remained intact in CA1 cells until death. Immunohistochemical staining for cytoplasmic dynein and kinesin, which are involved in the shuttle movement of mitochondria between cell body and the periphery, also showed early and progressive decreases after ischemia, and the decreases were found exclusively in the vulnerable CA1 subfield. A disturbance of mitochondrial DNA expression may be caused by dysfunction of the mitochondrial shuttle system and could cause progressive failure of energy production of CA1 neurons that eventually results in cell death. Thus, the mitochondrial hypothesis could provide a new and exciting potential for elucidating the mechanism of the delayed neuronal death of hippocampal CA1 neurons.

Neuronal Necrosis After Middle Cerebral Artery Occlusion in Wistar Rats Progresses at Different Time Intervals in the Caudoputamen and the Cortex

Article

May 1995

Most brain lesions that develop after an artery is occluded evolve from an initial stage of "ischemic injury" (probably reversible) to an infarct or an area where most neurons become necrotic. There is scant information on the time that must elapse after the arterial occlusion for neurons to undergo irreversible injury. The objective of these experiments was to chart the time course and the topographic distribution of the neuronal necrosis that follows the occlusion of a large cerebral artery. One hundred fifty-one adult rats (including 15 controls) were used in this study. One hundred forty-seven had the right middle cerebral artery occluded for variable periods ranging from 30 minutes to 7 days. After processing the brains for histology, a meticulous structural evaluation of each specimen, including quantitation of necrotic neurons, was followed by a detailed statistical analysis of the neuronal counts. Few neurons in isolated sites showed morphological signs of necrosis during the initial 4 hours; the first significant increase in the percentage of necrotic neurons (15%) was observed within the territory of the occluded artery after 6 hours (P < .05); 12 hours after the arterial occlusion most neurons (65%) had become necrotic (P < .0001). Pannecrosis involving neurons, glial cells, and blood vessels was observed at 72 to 96 hours. However, even at this time pannecrosis involved only the preoptic area and the lateral putamen; a few intact neurons remained visible in the cortex, and scattered necrotic neurons could be identified beyond the edges of the "area of pallor," which does not become clearly demarcated until 4 to 5 days after the arterial occlusion. There is a predictable progression in the development of neuronal necrosis after a permanent arterial occlusion. Irreversible changes appear first in the caudoputamen and then spread to the cortex. The causes for the progression of the lesion are not known; however, therapeutic interventions that start within the first 1 to 2 hours after the arterial occlusion may alter the histopathologic responses to this form of injury. It remains to be determined whether the extent of the neurological deficit induced by an arterial occlusion correlates with the number of necrotic neurons.

Neurological Deficit and Extent of Neuronal Necrosis Attributable to Middle Cerebral Artery Occlusion in Rats: Statistical Validation

Article

May 1995

Occluding a large intracranial artery in rats produces a brain lesion that grows in terms of an increase in both surface area and number of necrotic neurons. The present study investigated whether reperfusing the ischemic territory 30 to 60 minutes after the arterial occlusion would have a beneficial effect on either the clinical or the histological outcome of the lesion. One hundred four adult rats (including appropriate controls) were used; 97 had a middle cerebral artery occluded by inserting a nylon monofilament via the right external carotid artery. The arterial occlusion was transient in two groups and permanent in another; survival times were comparable for all groups. Control animals were subjected to a sham operation during which the artery was occluded for less than 1 minute. The outcome was evaluated by measuring the extent of the neurological deficit and the severity of the histological injury. Mean neurological score and mean number of necrotic neurons in the cortex were more favorable after transient (30- to 60-minute) compared with permanent arterial occlusion (P < .005). Moreover, the correlation between mean neurological score and mean number of necrotic neurons was highly significant: r = .951; P < .001. The histological effects of an intracranial arterial occlusion in the adult rat can be predicted on day 1 by the neurological score described in this report. Significant improvement can be obtained in these animals by reestablishing arterial flow 60 minutes or sooner after the ictus. The pattern of cortical pannecrosis observed after permanent occlusion (> or = 72 hours) was transformed into incomplete ischemic injury in most instances of transient occlusion.

Combined Perfusion and Diffusion-Weighted Magnetic Resonance Imaging in a Rat Model of Reversible Middle Cerebral Artery Occlusion

Article

Apr 1995

Diffusion-weighted imaging and dynamic first-pass bolus tracking of susceptibility contrast agents (perfusion imaging) are two new magnetic resonance imaging techniques that offer the possibility of early diagnosis of stroke. The present study was performed to evaluate the diagnostic information derived from these two methods in a rat model of temporary focal ischemia. Fifteen male Wistar rats were assigned to 45 (n = 7) or 120 minutes (n = 8) of middle cerebral artery occlusion followed by reperfusion using the intraluminal filament technique. The diffusion-weighted images were collected, and areas of hyperintensity were compared with histologically assessed areas of ischemic injury. The magnetic resonance perfusion image series were postprocessed to produce topographic maps reflecting the maximum reduction in the signal obtained during the first passage of the contrast agent and the time delay between the arrival of the bolus and the point of maximum contrast-agent effect. Hyperintensity in diffusion-weighted images was demonstrated after 30 minutes of middle cerebral artery occlusion and was mainly expressed in the lateral caudoputamen and parts of the lower frontoparietal cortex. Reperfusion after 45 minutes of occlusion reduced the area of hyperintensity from 24.2% to 9.9% of hemispheric area. In the group with 120 minutes of occlusion, the hyperintense area increased from 24.4% to 29.1%. Relative to the nonischemic hemisphere, the changes in the topographic maps of maximum signal reduction occurred in the lateral caudoputamen and adjacent lower neocortical areas. Increased time delay to maximum effect, however, was seen also in the upper frontoparietal cortex. Hyperintensity in diffusion-weighted images was reversible after 45 minutes but not after 120 minutes of middle cerebral artery occlusion. Analysis of the signal-reduction and time-delay parametric maps demonstrated regions of different perfusion changes in the ischemic hemisphere.

Water Diffusion and Acute Stroke

Article

Feb 1994

The occlusion of the middle cerebral artery was used as an experimental acute stroke model in 30 cats. The diffusion of water was followed by diffusion-sensitized MRI between 1 and 15 h after induction of stroke. It is demonstrated that images representing the trace of the diffusion tensor provide a much more accurate delineation of affected area than images representing the diffusion in one direction only. The reason is that the strong contrast caused by the anisotropy and orientation of myelin fibers is completely removed in the trace of the diffusion tensor. The trace images show a small contrast between white and gray matter. The diffusion coefficient of white matter is decreased in acute stroke to approximately the same extent as gray matter. It is further shown that the average lifetime of water in extra and intracellular space is shorter than 20 ms both for healthy and ischemic tissue indicating that myelin fibers are permeable to water. The anisotropy contrast did not change before or after induction of stroke, nor after sacrifice. Together, these observations are consistent with the view that the changes in water diffusion during acute stroke are directly related to cytotoxic oedema, i.e., to the change in relative volume of intra- and extracellular spaces. Changes in membrane permeability do not appear to contribute significantly to the changes in diffusion.

Davis D, Ulatowski J, Eleff S, Izuta M, Mori S, Shungu D, Van Zijl PCMRapid monitoring of changes in water diffusion coefficients during reversible ischemia in cat and rat brain. Magn Res Med 31:454-460

Article

Apr 1994

Changes in the diffusion constant of water during reversible brain ischemia and cardiac arrest were monitored with a 10-s time resolution. Results (five cats, three rats) indicate that these changes are reversible and that the bulk of the changes are not caused by temperature or motion related to brain pulsations and blood flow. The rapid time course of the changes corresponds to the known time course for changes in energy state, signal transduction, and ionic homeostasis.

Measurement of cerebrovascular changes in cats after transient ischemia using dynamic MRI

Article

Apr 1993

Hemodynamic changes associated with acute ischemia cannot be measured with conventional nuclear magnetic resonance imaging. In this study, we used dynamic susceptibility-contrast magnetic resonance imaging to measure the changes in vascular transit time and relative cerebral blood volume in a feline occlusion-reperfusion model. Dynamic susceptibility-contrast measurements were obtained before and during 10 minutes of global cerebral ischemia and for up to 3 hours after the onset of reperfusion. A cerebral blood flow index was calculated from the vascular transit time and relative cerebral blood volume measurements. Functional maps were constructed to demonstrate the regional hemodynamic differences resulting from the induced ischemia. During the early phase after reperfusion, both the relative cerebral blood volume and blood flow index rose sharply, followed by a fall to near-basal levels at 45 minutes (1 x control and 1.3 x control, respectively). Thereafter, the volume rose slowly, whereas the flow index continued to drop. At 3 hours, cerebral blood volume had reached 1.6 times its control value, whereas the flow index had returned to its base value. The hemodynamic behavior we observed in our model reflects the independent responses of the cerebral blood volume and flow index to ischemic insult. Measurements acquired by our method were consistent with the temporal behavior reported in previous radionuclide studies. Susceptibility-contrast nuclear magnetic resonance tomographic imaging proved to be valuable in detecting and quantifying both immediate and subsequent changes in the hemodynamic state of the ischemic and hyperemic feline brain.

Ischemic Stroke and Incomplete Infarction

Article

May 1996

The concept of selective vulnerability or selective loss o f individual neurons, with survival of glial and vascular elements as one of the consequences of a systemic ischemic-hypoxic insult (eg, transient cardiac arrest or severe hypotension), has been recognized for decades. In contrast, selective neuronal death as one of the lesions that may develop in the brain after occluding an intracranial artery is an idea not readily acknowledged in the current medical literature dealing with human stroke. A review of pertinent publications reveals that selective neuronal injury after middle cerebral artery occlusion was observed in autopsy specimens over 40 years ago, although its pathogenesis remains unclear. Recent observations in both humans and animals suggest that selective neuronal necrosis (rather than infarct) is the consequence of either a short-term arterial occlusion or permanent occlusion accompanied by ischemia of moderate severity. During the acute and subacute states of an ischemic stroke, the loss of a limited number of neurons (ie, incomplete infarction) does not result in structural changes discernible by either CT or conventional MRI. However, the loss of a selected number of neurons may be demonstrable in vivo by calculating the corresponding loss of benzodiazepine receptors. The use of specific radiotracers in combination with single-photon emission CT or positron emission tomography allows demonstration of a decrease in gamma-aminobutyric acid-ergic receptor sites at places where many neurons have been lethally injured. We aim to alert physicians to the potential development of incomplete brain infarctions in patients with intracranial arterial occlusions. Recognizing incomplete infarcts is particularly important in the context of stroke therapy with thrombolytic and neuroprotective agents. This brain lesion is likely to be the consequence of an arterial occlusion with a resultant ischemia of moderate severity (eg, regional blood flows in the range of 15 to 20 mL x 100 g-1 x min-1).

Acute and chronic stroke: Navigated spin-echo diffusion-weighted MR imaging

Article

Jun 1996

The authors evaluated a phase-navigated spin-echo (SE) motion-correction sequence for use at diffusion-weighted (DW) magnetic resonance (MR) imaging after cerebral infarction. Twenty-nine patients underwent 32 conventional T2-weighted fast SE and SE DW imaging after stroke (n=25), transient ischemic attack (n=3), or reversible ischemic neurologic deficit (n=1). Imaging was performed in a standard head holder with standard padding. Apparent diffusion coefficient (ADC) maps were constructed. DW images depicted high signal intensity compatible with localization of the ischemic symptoms in all cases. Lesions were depicted more clearly on DW than on T2-weighted images. On DW images, acute infarct ADC values were uniformly low (mean, 0.401x10(-5) cm2/sec =+/- 0.143 [standard deviation]) compared with control ADC values (mean, 0.754x10(-5) cm2/sec +/- 0.201). ADC values of chronic infarcts were supranormal (mean, 1.591x10(-5) cm2/sec +/- 0.840) compared with control values (mean, 0.788x10(-5) cm2/sec +/- 0.166). DW imaging did not show a change after transient ischemic attack. with reversible ischemic neurologic deficit, however, hyperintensity on DW images and low ADC resolved after symptoms abated. Clinical phase-navigated SE DW imaging improved early diagnosis of stroke and helped differentiate acute from chronic stroke. Changes on DW images are reversed after symptoms resolve.

Incomplete Brain Infarction of Reperfused Cortex May Be Quantitated With Iomazenil

Article

Feb 1997

[123I]Iomazenil is a specific radioligand for the central benzodiazepine receptor that may be useful as an indicator of the intactness of cortical neurons after focal cerebral ischemia. We evaluated the binding of this receptor in reperfused cortex among patients with ischemic stroke to detect viable neurons in cortex that appeared structurally intact on conventional neuroimaging studies. Fourteen patients were selected by (1) angiography within 24 hours of onset showing embolic occlusion of an intracranial artery, (2) cerebral blood flow showing ischemia of moderate severity in 12 cases and spontaneous reflow in 2 cases, and (3) thrombolysis with reperfusion within 24 hours in most cases. Thirty reperfused cortical areas that remained structurally intact, 7 infarcted cortical areas, and 6 contralateral cerebellar areas with reduced blood flow were selected as regions of interest to estimate receptor binding 5 days to 23 months after the stroke. A two-compartment model was used to compute the distribution volume (Vd) of iomazenil in relative units, with Vd proportional to benzodiazepine receptor concentration. The side-to-side asymmetry ratio of Vd was calculated. The mean asymmetry ratio was 0.89 +/- 0.11 (range, 0.64 to 1.05), 0.50 +/- 0.15 (range, 0.23 to 0.67), and 0.97 +/- 0.05 (range, 0.90 to 1.04) in reperfused cortex, infarcted cortex, and contralateral cerebellum, respectively. Compared with unity, both reperfused cortex and infarcted cortex showed significant decrease of Vd (P < .001). Contralateral cerebellum showing diaschisis had no reduction of Vd. On MRI, obtained 3 or 6 months after the stroke, mild cortical atrophy was observed in two reperfused areas where the asymmetry ratio was moderately reduced (0.64 and 0.80). The reduction of benzodiazepine receptor concentration in reperfused cortex that remained structurally intact is likely to be the result of injury involving only a limited number of neurons (ie, incomplete infarction). Our data suggest that the degree of viability of ischemic cortex apparently salvaged by early reperfusion can be quantified by iomazenil.

Clinical utility of diffusion-weighted magnetic resonance imaging in the assessment of ischemic stroke

Article

May 1997

Diffusion-weighted imaging (DWI) detects small changes in water diffusion that occur in ischemic brain. This study evaluated the clinical usefulness of a phase-navigated spin-echo DWI sequence compared with T2-weighted magnetic resonance imaging (T2W MRI) in patients with cerebral ischemia and assessed apparent diffusion coefficient (ADC) and T2-weighted imaging (T2WI) changes over time. ADC values and T2 ratios of image intensity were measured from the region of ischemia and from the corresponding contralateral brain region. The clinical histories of patients with DWI scans obtained over the course of 1 year were reviewed to ascertain whether DWI aided in clinical diagnosis or management. Of 103 scans obtained a mean of 10.4 days after symptom onset, DWI detected six lesions not seen on T2WI and discriminated two new infarcts from old lesions. DWI was most useful within 48 hours of the ictus. The evolution of ADC values and T2 ratios was evaluated in 26 cases with known symptom onset times. ADC values were low at less than 1 week after stroke onset and became elevated at chronic time points. T2 ratios were near normal acutely, increasing thereafter. DWI was superior to T2W MRI in detecting acute stroke, whereas both techniques assisted in determining lesion age.

Early Detection of Irreversibly Damaged Ischemic Tissue by Flumazenil Positron Emission Tomography in Cats

Article

Nov 1997

Ligands for cerebral benzodiazepine receptors were used in the past to indicate the intactness of cortical neurons in subacute to chronic states after stroke and thus to differentiate among brain regions with complete or incomplete infarction and with functional deactivation. For planning acute interventional therapy, however, a marker of irreversible damage in early ischemia is needed. We studied the applicability of [11C]flumazenil (FMZ) for differentiation between tissue with and without potential of recovery in the first hours after focal experimental ischemia. In 11 cats, cerebral blood flow, cerebral metabolic rate for oxygen, oxygen extraction fraction, and FMZ binding were studied repeatedly by positron emission tomography before, during, and up to 12 hours after transient middle cerebral artery occlusion (MCAO) (30 minutes in 2, 60 minutes in 7, and 120 minutes in 2 cats, respectively). Development of the defects in energy metabolism were compared with the defects in FMZ binding (2 to 3 hours and 8 to 9 hours after MCAO), with the pattern of disturbed glucose metabolism (determined 12 hours after MCAO), and with the size of the infarcts (determined approximately 15 hours after MCAO). Irrespective of the level of reperfusion, defects in FMZ binding (2 to 3 hours after MCAO) were closely related to areas with severely depressed oxygen consumption and predicted the size of the final infarcts, whereas preserved FMZ binding indicated intact cortex. Depression of glucose metabolism was in all animals larger than the defects in FMZ binding and the infarcts, indicating functional deactivation of brain areas beyond the permanent morphological damage. In addition, FMZ distribution within 2 minutes after injection was significantly correlated to flow and yielded reliable perfusion images. The reduction of FMZ binding early after focal ischemia reflects irreversible neuronal damage that otherwise only can be detected by multitracer studies. Our experimental data and first clinical applications suggest that FMZ has potential as an indicator of developing infarction. Since FMZ distribution additionally images perfusion, this tracer might be useful for the selection of patients who would benefit from acute therapeutic intervention.

Incomplete Infarct and Delayed Neuronal Death After Transient Middle Cerebral Artery Occlusion in Rats

Article

Nov 1997

The clinical syndrome of transient ischemic attacks is accompanied in a significant percentage of patients by brain lesions or neuroimaging abnormalities whose structural counterparts have not been defined. The objective of this study was to analyze, in an experimental model of short-term (< 25 minutes) focal ischemia and long-term (< or = 28 days) reperfusion, the extent and nature of the structural abnormalities affecting neurons and glia located within the territory of the transiently occluded artery. Adult Wistar rats (n = 121) had the origin of one middle cerebral artery (MCA) occluded with a nylon monofilament for periods of 10 to 25 minutes. Experiments of transient MCA occlusion were terminated at variable periods ranging from 1 day to 4 weeks. Control experiments consisted of (1) MCA occlusion without reperfusion (n = 7) lasting 7 to 14 days and (2) sham operations (n = 2) followed by 1- to 4-day survival. After in situ fixation, brain specimens were serially sectioned and subjected to detailed morphometric evaluations utilizing light and electron microscopes. The statistical method used to evaluate the results was based on ANOVA followed by Bonferroni's corrected t test and Student's t test comparisons. Brain lesions were not detectable in the sham-operated controls. All brains with permanent MCA occlusion (7 to 14 days) had large infarctions with abundant macrophage infiltration and early cavitation. Forty-five (37%) of the experiments involving transient MCA occlusion had no detectable brain lesions after 4 weeks. Selective neuronal necrosis was found in 76 of 121 rats (63%) with transient MCA occlusion. Neuronal necrosis always involved the striatum, and in 29% of the brains with ischemic injury, necrosis also included a short segment of the cortex. In the striatum, the length of the arterial occlusion was the main determinant of the number of necrotic neurons (20 minutes [22.6 +/- 19] is worse than 10 minutes [4.9 +/- 7]) (P < .0001). In the cortex, the length of reperfusion determined the number of necrotic neurons appearing in layer 3. Experiments with reperfusion of 4 to 7 days' duration yielded more necrotic neurons per microscopic field (2.02 +/- 3) than those lasting fewer days (0.04 +/- 0.1) (P < .05). The histological features of these lesions underwent continuous change until the end of the fourth week, at which time necrotic neurons were still visible both in the striatum and in the cortex. Arterial occlusions of short duration (< 25 minutes) produced, in 76 of 121 experiments (63%), brain lesions characterized by selective neuronal necrosis and various glial responses (or incomplete infarction). This lesion is entirely different from the pannecrosis/cavitation typical of an infarction that appears 3 to 4 days after a prolonged arterial occlusion. Delayed neuronal necrosis, secondary to a transient arterial occlusion or increasing numbers of necrotic neurons in experiments with variable periods of reperfusion, was a response observed only at a predictable segment of the frontoparietal cortex.

Regional Ischemia and Ischemic Injury in Patients With Acute Middle Cerebral Artery Stroke as Defined by Early Diffusion-Weighted and Perfusion-Weighted MRI

Article

Jun 1998

We sought to map early regional ischemia and infarction in patients with middle cerebral artery (MCA) stroke and compare them with final infarct size using advanced MRI techniques. MRI can now delineate very early infarction by diffusion-weighted imaging (DWI) and abnormal tissue perfusion by perfusion-weighted imaging (PWI). Seventeen patients seen within 12 hours of onset of MCA stroke had MR angiography, standard MRI, and PWI and DWI MRI. PWI maps were generated by analysis of the passage of intravenous contrast bolus through the brain. Cerebral blood volume (CBV) was determined after quantitative analysis of PWI data. Volumes of the initial DWI and PWI lesion were calculated and compared with a final infarct volume from a follow-up imaging study (CT scan or MRI). Group 1 (10 patients) had MCA stem (M1) occlusion by MR angiography. DWI lesion volumes were smaller than the volumes of CBV abnormality. In 7 patients the final stroke volume was larger or the same, and in 3 it was smaller than the initial CBV lesion. Group 2 (7 patients) had an open M1 on MR angiography with distal MCA stroke. In 6 group 2 patients, the initial DWI lesion matched the initial CBV abnormality and the final infarct. Most patients with M1 occlusion showed progression of infarction into the region of abnormal perfusion. In contrast, patients with open M1 had strokes consistent with distal branch occlusion and had maximal extent of injury on DWI at initial presentation. Application of these MRI techniques should improve definition of different acute stroke syndromes and facilitate clinical decision making.

A New Method to Improve In-Bore Middle Cerebral Artery Occlusion in Rats Demonstration With Diffusion- and Perfusion-Weighted Imaging

Article

Sep 1998

In-bore middle cerebral artery occlusion (MCAO) enables investigators to acquire preischemic MRI data and to image ischemic changes immediately after occlusion. We have developed a highly successful in-bore MCAO method. This study describes the methods and pertinent techniques. Sixty-seven Sprague-Dawley rats were subjected to temporary (n=36) or permanent (n=31) MCAO. The occluding device consisted of a supporting tubing, a driving line, and a silicone-coated 4-0 nylon suture occluder. Outside the magnet, the occluder was positioned in the carotid canal. MCAO was achieved in the magnet bore by remotely advancing the driving line until resistance was felt. Diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) were acquired before and immediately after occlusion and were used to document the presence of MCAO. Fifty-nine (88.1%) rats were successfully occluded, demonstrating hyperintensity on DWI, perfusion deficits on PWI, and no subarachnoid hemorrhage at postmortem examination. The average values of the apparent diffusion coefficient in both the frontoparietal cortex and the lateral caudoputamen significantly decreased as early as 3 minutes after the onset of ischemia. The failures included preocclusion damage (1/67), sliding out of the occluder during occlusion (1/67), no occlusion (2/67), and arterial perforation (4/67). Our in-bore MCAO method is easily performed and is as successful as MCAO induced outside the magnet.

Diffusion-Weighted Magnetic Resonance Imaging in Acute Stroke

Article

Sep 1998

Diffusion-weighted MRI (DWI) is highly sensitive in detecting early cerebral ischemic changes in acute stroke patients. In this study we compared the sensitivity of DWI with that of conventional MRI techniques. Furthermore, we investigated the prognostic value of the volume of ischemic lesions on DWI scans and of the apparent diffusion coefficient (ADC). We performed DWI, fluid-attenuated inversion recovery, spin-echo T2-weighted MRI, and spin-echo proton density-weighted MRI in 42 patients with acute stroke and 15 control subjects. The volume of ischemic lesions was measured on early (<60 hours after onset) and follow-up MRI scans. Clinical outcome was measured 4 months after onset of symptoms with the National Institutes of Health Stroke Scale, the Barthel Index, and the Rankin Scale. With DWI, 98% of the ischemic lesions were detected, and with fluid-attenuated inversion recovery, 91% were detected, whereas with early T2-weighted or proton density-weighted scans, only 71% (P=0.002, chi2) and 80% (P=0.02, chi2) of lesions, respectively, were found. Lesion volume on early DWI scans correlated significantly with clinical outcome ratings (P<0.01). In patients with a first-ever stroke, a lesion volume of < or =22 mL on DWI predicted good outcome with a 75% sensitivity and a 100% specificity. The mean ADC of ischemic lesions was 29% lower than the ADC of normal-appearing parts of the brain (P<0.001). The ADC ratio correlated significantly with clinical outcome (P<0.05). DWI is a better imaging method than conventional MRI in detecting early ischemic lesions in stroke patients. Lesion size as measured on DWI scans and, to a lesser extent, ADC values are potential parameters for predicting clinical outcome in acute stroke patients.

Is the Cell Death Pathway Triggered by the Mitochondrion or the Endoplasmic Reticulum?

Article

Feb 1999

Ca2+i, free cytosolic calcium concentration; CsA, cyclosporin A; ER, endoplasmic reticulum; IP3, inositol trisphosphate; MPT, mitochondrial permeability transition

Resolution of early diffusion-weighted and FLAIR MRI abnormalities in a patient with TIA

Article

Apr 1999

We report a patient with a clinical history and neurologic examination consistent with acute stroke. Diffusion-weighted and fast fluid-attenuated inversion recovery MRI obtained 4 hours after stroke onset detected focal abnormalities suggestive of acute ischemic brain damage. The neurologic deficit and the imaging abnormalities both resolved completely at follow-up. This patient illustrates complete resolution of early changes observed with diffusion-weighted MRI at the hyperacute phase in a TIA.

Confusional State in Stroke : Relation to Preexisting Dementia, Patient Characteristics, and Outcome

Article

May 1999

Acute confusional state (ACS) is frequent in hospitalized stroke patients. We previously showed that 16% of patients admitted for a stroke have preexisting dementia. The extent to which preexisting cognitive decline is associated with a risk of ACS at the acute stage of stroke remains to be systematically examined. The aim of this study was to evaluate the prevalence of ACS in acute stroke patients, to study the influence of preexisting cognitive decline and other patient characteristics, and to evaluate the influence of ACS on outcome. We diagnosed ACS using DSM-IV criteria and the Delirium Rating Scale with a cutoff of 10 in 202 consecutive stroke patients aged 40 years or older (median age, 75 years; range, 42 to 101 years). Cognitive functioning before stroke was assessed with the Informant Questionnaire on Cognitive Decline in the Elderly. Forty-nine stroke patients (24.3%; 95% CI, 18.3% to 30.2%) had an ACS during hospitalization. Using logistic regression analysis, we found preexisting cognitive decline (P=0.006) and metabolic or infectious disorders (P=0.008) to be independent predictors of ACS. Functional, but not vital, prognosis was worse in patients with ACS at discharge and 6 months after stroke. ACS occurs in one fourth of stroke patients older than 40 years. Its occurrence requires inquiry for a preexisting cognitive decline, which usually remains unrecognized in the absence of a systematic evaluation.

Novel Brain Ischemic Change on MRI Delayed Ischemic Hyperintensity on T1-Weighted Images and Selective Neuronal Death in the Caudoputamen of Rats After Brief Focal Ischemia

Article

Jun 1999

Specific change of persistent hyperintensity/hypointensity on T1-weighted (T1W) and T2-weighted (T2W) MRI, respectively, has been reported to develop in the human basal ganglia after brief hemispheric ischemia. We investigated whether this ischemic change observed in humans could be reproduced experimentally in rats after brief middle cerebral artery (MCA) occlusion (MCAO), and if so, what the neuroradiological change represented histologically. The origin of the right MCA of male Wistar rats (n=25) was occluded for 15 minutes by inserting a silicon-coated nylon thread from the external carotid artery into the internal carotid artery. After 15 minutes' MCAO, coronal MR images (T1W, T2W, and T1W with fat saturation pulse) were obtained once at 3-day reperfusion (n=5) and twice at 3- and 7-day reperfusion (n=20). Brain specimens were examined histologically immediately after the last MRI study in all rats. Neither T1W nor T2W MRI showed marked signal changes 3 days after reperfusion following 15-minute MCAO. However, the ischemic change of hyperintensity and hypointensity on T1W and T2W MRI, respectively, appeared in the striatum following 7-day reperfusion after 15-minute MCAO (n=19/20). Histological examination revealed that the specific lesion in the rat striatum on MRI corresponded to selective neuronal death and proliferation of reactive astrocytes and microglia without infarct, hemorrhage, lipid accumulation, or calcification. Brief MCAO with reperfusion induces the delayed ischemic changes of hyperintensity and hypointensity on T1W and T2W MRI, respectively, in the rat striatum with high reproducibility. This specific ischemic change on MRI histologically corresponded to selective neuronal death and gliosis with preservation of the macroscopic structure of the brain. A similar MRI pattern reported in patients who have sustained brief ischemia may represent similar histology. We speculate that the ischemic change reflects some biochemical changes affecting the magnetic field as the brain tissue undergoes subtle structural changes.

Delayed Ischemic Hyperintensity on T1-Weighted MRI in the Caudoputamen and Cerebral Cortex of Humans After Spectacular Shrinking Deficit

Article

Jun 1999

Transient internal carotid artery (ICA)-middle cerebral artery (MCA) occlusion caused by cardiogenic embolus can lead to spectacular shrinking deficit (SSD): sudden hemispheric stroke syndrome followed by rapid improvement. The aim of this study was to investigate sequential neuroradiological changes in the brains of patients after SSD compared with those after brief cardiac arrest and hypoglycemia, which we previously studied with the same methods. We serially studied CT scans and MR images obtained at 1.5 T in 4 patients with SSD. All 4 patients suffered from transient neurological deficits due to cardiogenic embolus in ICA-MCA. The symptoms began to disappear from 25 to 50 minutes after onset. Repeated CT scans demonstrated no abnormal findings in the affected cerebral hemisphere in 3 of the 4 patients and a small cortical infarct in the remaining 1. In each patient, repeated MRI between day 7 and month 23 after stroke showed basal ganglionic and cortical lesions. These lesions were hyperintense on T1-weighted and relatively hypointense on T2-weighted imaging. These ischemic lesions of hyperintensity on T1-weighted MRI subsided with time. Transient ICA-MCA occlusion leading to SSD produces a specific ischemic change with delayed onset in the basal ganglia and cerebral cortex in humans on MRI but not CT scans. We speculate that the lesions represent incomplete ischemic injury, including selective neuronal death, proliferation of glial cells, paramagnetic substance deposition, and/or lipid accumulation. Unlike brief cardiac arrest or hypoglycemia, the localized lesions on MRI of patients after SSD seem to be incomplete and to differ from infarction or hemorrhage.

Diffusion MRI in Patients With Transient Ischemic Attacks

Article

Jul 1999

Diffusion MRI has established value in patients with ischemic stroke but has not been systematically investigated in patients with transient ischemic attack (TIA). Clinical, conventional MRI, and diffusion MRI data were collected on 42 consecutive patients with symptoms of cerebral TIA. TIA imaging data were compared with those from a contemporaneous group of 23 completed stroke patients. Twenty of the 42 TIA patients (48%) demonstrated neuroanatomically relevant focal abnormalities on diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) imaging. When present, DWI/ADC signal changes in TIA patients were less pronounced and smaller in volume than those in completed stroke patients. TIA symptom duration was significantly longer for DWI-positive than for DWI-negative patients, 7.3 versus 3.2 hours. Diffusion MRI information changed the suspected anatomic and vascular TIA localization and the suspected etiologic mechanism in over one third of patients with diffusion MRI abnormalities. Of the 20 TIA patients with identifiable lesions on diffusion MRI, 9 had follow-up imaging studies; of these, 4 did not show a relevant infarct on follow-up imaging. Diffusion MRI demonstrates ischemic abnormalities in nearly half of clinically defined TIA patients. The percentage of patients with a DWI lesion increases with increasing total symptom duration. In nearly half, the diffusion MRI changes may be fully reversible, while in the remainder the diffusion MRI findings herald the development of a parenchymal infarct despite transient clinical symptoms. Finally, diffusion imaging results have significant clinical utility, frequently changing the presumed localization and etiologic mechanism.

Normal diffusion-weighted MRI during stroke-like deficits

Article

Jul 1999

Diffusion-weighted MRI (DWI) represents a major advance in the early diagnosis of acute ischemic stroke. When abnormal in patients with stroke-like deficit, DWI usually establishes the presence and location of ischemic brain injury. However, this is not always the case. To investigate patients with stroke-like deficits occurring without DWI abnormalities in brain regions clinically suspected to be responsible. We identified 27 of 782 consecutive patients scanned when stroke-like neurologic deficits were still present and who had normal DWI in the brain region(s) clinically implicated. Based on all the clinical and radiologic data, we attempted to arrive at a pathophysiologic diagnosis in each. Best final diagnosis was a stroke mimic in 37% and a cerebral ischemic event in 63%. Stroke mimics (10 patients) included migraine, seizures, functional disorder, transient global amnesia, and brain tumor. The remaining patients were considered to have had cerebral ischemic events: lacunar syndrome (7 patients; 3 with infarcts demonstrated subsequently) and hemispheric cortical syndrome (10 patients; 5 with TIA, 2 with prolonged reversible deficits, 3 with infarction on follow-up imaging). In each of the latter three patients, the regions destined to infarct showed decreased perfusion on the initial hemodynamically weighted MRI (HWI). Normal DWI in patients with stroke-like deficits should stimulate a search for nonischemic cause of symptoms. However, more than one-half of such patients have an ischemic cause as the best clinical diagnosis. Small brainstem lacunar infarctions may escape detection. Concomitant HWI can identify some patients with brain ischemia that is symptomatic but not yet to the stage of causing DWI abnormality.

Reversal of acute apparent diffusion coefficient abnormalities and delayed neuronal death following transient focal cerebral ischemia in rats

Article

Sep 1999

Twenty-two rats were subjected to 8, 15, 30, or 60 minutes of temporary middle cerebral artery occlusion (n = 5 per group) or sham occlusion (n = 2) in the magnetic resonance imaging unit. Diffusion-, perfusion-, and T2-weighted imaging were acquired before and during occlusion, and after reperfusion. A coregistration method was used to correlate the acute changes of the average apparent diffusion coefficient (ADCav) with the histology after 72 hours at the same topographic sites. The initially reduced ADCav values recovered completely in both the lateral caudoputamen and upper frontoparietal cortex in the 8-, 15-, and 30-minute groups, partially in the cortex, and not at all in the caudoputamen in the 60-minute group. The histology showed that the caudoputamen was either normal or had mild neuronal injury in the 8-minute group and invariably had some degree of neuronal death in the 15-, 30-, and 60-minute groups, whereas the cortex was either normal or had varying degrees of neuronal injury in all groups. No histological abnormalities were seen in the sham-operated rats. Our data suggest that acute ADCav reversal does not always predict tissue recovery from ischemic injury and that temporary focal ischemia for even 8-minute duration can cause delayed neuronal death that is more severe in the caudoputamen where the initial ADCav decline was greater than in the cortex.

The ischemic penumbra: Operationally defined by diffusion and perfusion MRI

Article

Nov 1999

Identifying tissue at risk for infarction is important in deciding which patients would benefit most from potentially harmful therapies and provides a way to evaluate newer therapies with regard to the amount of ischemic tissue salvaged. To operationally define and characterize cerebral tissue at risk for stroke progression. We retrospectively selected 25 patients with an acute onset of a hemispheric stroke from our database who had undergone a combination of two diffusion-weighted MRI studies and a perfusion-weighted MRI study. We applied a logistic regression model using maps of the relative mean transit time and relative cerebral blood flow (rCBF) as well as three different maps of the relative cerebral blood volume (rCBV) to predict an operationally defined penumbra (region of mismatch between the diffusion lesion on day 1 and its extension 24 to 72 hours later). Maps of the rCBF and initial rCBV were significant predictors for identifying penumbral tissue. Our operationally defined penumbral region was characterized by a reduction in the initial rCBV (47% of contralateral control region [CCR]), an increase (163% of CCR) in the total rCBV, and a reduction (37% of CCR) in the rCBF, whereas the operationally defined ischemic core showed a more severe reduction in the rCBF (12% of CCR) and in the initial rCBV (19% of CCR). These MR indexes may allow the identification and quantification of viable but ischemically threatened cerebral tissue amenable to therapeutic interventions in the hyperacute care of stroke patients.

Early detection of regional cerebral ischemia in cats: comparison of diffusion-and T 2 -weighted MRI and spectroscopy

Jan 1990
330-346

Me Moseley
Y Cohen
J Mintorovitch
L Chileuitt
H Shimizu
J Kucharczyk
Mf Wendland
Pr Weinstein

Moseley ME, Cohen Y, Mintorovitch J, Chileuitt L, Shimizu H, Kucharczyk J, Wendland MF, Weinstein PR. Early detection of regional cerebral ischemia in cats: comparison of diffusion-and T 2 -weighted MRI and spectroscopy. Magn Reson Med. 1990;14:330 –346.

Rapid monitoring of changes in water diffusion coefficients during reversible ischemia in cat and rat brain

Jan 1994
454-460

D Davis
J Ulatowski
S Eleff
M Izuta
S Mori
D Shungu
Pcm Van Zijl

Davis D, Ulatowski J, Eleff S, Izuta M, Mori S, Shungu D, van Zijl PCM. Rapid monitoring of changes in water diffusion coefficients during reversible ischemia in cat and rat brain. Magn Reson Med. 1994;31:454 – 460.

Transient and permanent resolution of ischemic lesions on diffusion-weighted imaging after brief periods of focal ischemia in rats : correlation with histopathology

Abstract

No full-text available

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