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Marc Fisher

Publications and source records attributed to Marc Fisher.

At least 37 records · Page 2Linked to original sources
PubMed2005

Enhancing the development and approval of acute stroke therapies: Stroke Therapy Academic Industry roundtable.

BACKGROUND: Previous Stroke Therapy Academic Industry Roundtable (STAIR) meetings focused on preclinical evidence of drug efficacy and enhancing acute stroke trial design and performance. A fourth (STAIR-IV) was held to discuss relevant issues related to acute stroke drug development and regulatory approval. SUMMARY OF REVIEW: The STAIR-IV meeting had 3 main focus areas. The first topic was novel approaches to statistical design of acute stroke trials and appropriate outcome measures. The second focus was the need for better cooperation among participants in stroke therapy development that may be addressed through a national consortium of stroke trial centers in the United States and elsewhere. Lastly, regulatory issues related to the approval of novel mono and multiple acute stroke therapies were discussed. CONCLUSIONS: The development of additional acute stroke therapies represents a large unmet need with many remaining challenges and also opportunities to incorporate novel approaches to clinical trial design that will lead to regulatory approval. The STAIR-IV meeting explored new concepts of trial methodology and data analysis, initiatives for implementing a US clinical trialist consortium, and pertinent regulatory issues to expedite approval of novel therapies.

Brain Ischemia↗
PubMed2005

Perfusion and diffusion imaging in acute focal cerebral ischemia: temporal vs. spatial resolution.

High-resolution diffusion- (DWI) and perfusion-weighted (PWI) imaging may provide substantial benefits in accurate delineation of normal, ischemic, and at-risk tissue. We compared the capability of low (400 x 400 microm(2)) and high (200 x 200 microm(2)) spatial resolution imaging in characterizing the spatiotemporal evolution of the ischemic lesion in a permanent middle artery occlusion (MCAO) model in rats. Serial measurements of cerebral blood flow (CBF) and the apparent diffusion coefficient (ADC) were performed. Lesion volumes were calculated by using viability thresholds or by visual inspection, and correlated with infarct volume defined by TTC staining at 24 h after MCAO. At the very early phase of ischemia, high-resolution resulted in a significantly larger ADC-derived lesion volume and a smaller PWI/DWI mismatch. At 3 h after MCAO, ADC and CBF lesions showed similar robust correlations with TTC-defined infarct volumes for both groups using previously established thresholds. When lesions were determined visually, low-resolution resulted in a substantial overestimation of TTC-defined infarct volume and a lower inter-observer reliability (r = 0.75), whereas high-resolution produced an excellent correlation with TTC-defined infarct volume and inter-observer reliability (r = 0.96). In conclusion, high-resolution MRI resulted in substantial temporal averaging of the ischemic lesion during the early phase, but was clearly superior in visual determination of final infarct size. Low-resolution reasonably evaluated the temporal and spatial evolution of ischemia when thresholds were used.

Acute Disease↗
PubMed2005

HMG-CoA reductase inhibitors improve acute ischemic stroke outcome.

BACKGROUND AND PURPOSE: Statins reduce the risk of stroke recurrence, but the benefits of statins in improving outcome of acute stroke patients have not been well explored. METHODS: We assessed potential effects of statins initiated before or within 4 weeks of stroke on 90-day outcome. Favorable outcomes were National Institutes of Health Stroke Scale (NIHSS) score < or =2 at 12 weeks and modified Rankin Scale (mRS) < or =2. RESULTS: Before stroke, 129 patients were receiving statins, 123 initiated statins within 4 weeks, and 600 patients were not on statins. Multivariate logistic regression analysis demonstrated that poststroke statins were associated with a significant probability of a favorable outcome at 12 weeks [NIHSS (P=0.002; OR, 1.92; CI, 1.27 to 2.91) and mRS (P=0.033; OR, 1.57; CI, 1.04 to 2.38)], whereas prestroke statins demonstrated a trend toward significance. CONCLUSIONS: These preliminary results suggest that statin use may improve outcome of acute ischemic stroke.

Aged↗
PubMed2005

Developing and implementing future stroke therapies: the potential of telemedicine.

Stroke is a major public health concern with few positive phase III clinical trials and a shortage of stroke care expertise. Drug development likely can be enhanced by adapting new outcome measures and following guidelines generated by consensus groups. To enhance rates of drug implementation and to improve stroke care, some states are requiring that acute care hospitals obtain primary stroke center certification, and this mandate necessitates that smaller hospitals join larger ones in stroke care networks. Cutting-edge technology in the form of telemedicine is being implemented in stroke care networks to combat the lack of stroke care expertise by extending the availability of physician stroke expertise. The telemedicine network can be used to transmit real-time data from stroke care-certified community hospitals (spokes) to a tertiary center (hub). Telemedicine can be used to educate physicians in spoke hospitals about new stroke treatments. The advent and development of telemedicine has the potential to ensure that patients with stroke have a greater opportunity to receive the full range of therapeutic options currently available and those that will become available in the future. The implementation of future drug therapies through telemedicine-organized stroke networks will likely substantially influence the future of acute stroke therapy.

Humans↗
PubMed2005

Visualization of cortical spreading depression using manganese-enhanced magnetic resonance imaging.

Cortical spreading depression (CSD) was visualized using manganese-enhanced MRI (MEMRI) following topical application of KCl to the exposed rat cortex. MEMRI signal increase in the ipsilateral cortex relative to the contralateral control region was 60 +/- 30% following two KCl applications. MEMRI signal increase for a single (40%) versus double (80%) KCl application suggests an integration effect over successive CSD episodes. CSD-induced MEMRI enhancement involved cortical layers containing dense regions of apical dendrites, supporting the contention that these neuronal structures are necessary for propagation of CSDs. Subcortical enhancement was present in hippocampal and thalamic regions, most likely a result of neuronal connections with cortical layers 4 and 5. These results are consistent with previous studies of CSD using diffusion-weighted MRI and T(2) (*)-weighted MRI and should be useful for investigating CSD itself and its role in other neurologic disorders.

Animals↗
PubMed2005

Effects of intravenous dimethyl sulfoxide on ischemia evolution in a rat permanent occlusion model.

Dimethyl sulfoxide (DMSO) has a variety of biological actions that suggest efficacy as a neuroprotectant. We (1) tested the neuroprotective potential of DMSO at different time windows on infarct size using 2,3,5-triphenyltetrazolium staining and (2) investigated the effects of DMSO on ischemia evolution using quantitative diffusion and perfusion imaging in a permanent middle cerebral artery occlusion (MCAO) model in rats. In experiment 1, DMSO treatment (1.5 g/kg intravenously over 3 h) reduced infarct volume 24 h after MCAO by 65% (P<0.00001) when initiated 20 h before MCAO, by 44% (P=0.0006) when initiated 1 h after MCAO, and by 17% (P=0.11) when started 2 h after MCAO. Significant infarct reduction was also observed after a 3-day survival in animals treated 1 h after MCAO (P=0.005). In experiment 2, treatment was initiated 1 h after MCAO and maps for cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) were acquired before treatment and then every 30 mins up to 4 h. Cerebral blood flow characteristics and CBF-derived lesion volumes did not differ between treated and untreated animals, whereas the ADC-derived lesion volume essentially stopped progressing during DMSO treatment, resulting in a persistent diffusion/perfusion mismatch. This effect was mainly observed in the cortex. Our data suggest that DMSO represents an interesting candidate for acute stroke treatment.

Animals↗
PubMed2005

Statistical prediction of tissue fate in acute ischemic brain injury.

An algorithm was developed to statistically predict ischemic tissue fate on a pixel-by-pixel basis. Quantitative high-resolution (200 x 200 microm) cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) were measured on acute stroke rats subjected to permanent middle cerebral artery occlusion and an automated clustering (ISODATA) technique was used to classify ischemic tissue types. Probability and probability density profiles were derived from a training data set (n=6) and probability maps of risk of subsequent infarction were computed in another group of animals (n=6) as ischemia progressed. Predictions were applied to overall tissue fate. Performance measures (sensitivity, specificity, and receiver operating characteristic) showed that prediction made based on combined ADC+CBF data outperformed those based on ADC or CBF data alone. At the optimal operating points, combined ADC+CBF predicted tissue infarction with 86%+/-4% sensitivity and 89%+/-6% specificity. More importantly, probability of infarct (P(I)) for different ISODATA-derived ischemic tissue types were also computed: (1) For the 'normal' cluster in the ischemic right hemisphere, P(I) based on combined ADC+CBF data (P(I)[ADC+CBF]) accurately reflected tissue fate, whereas P(I)[ADC] and P(I)[CBF] overestimated infarct probability. (2) For the 'perfusion-diffusion mismatch' cluster, P(I)[ADC+CBF] accurately predicted tissue fate, whereas P(I)[ADC] underestimated and P(I)[CBF] overestimated infarct probability. (3) For the core cluster, P(I)[ADC+CBF], P(I)[ADC], and P(I)[CBF] prediction were high and similar ( approximately 90%). This study shows an algorithm to statistically predict overall, normal, ischemic core, and 'penumbral' tissue fate using early quantitative perfusion and diffusion information. It is suggested that this approach can be applied to stroke patients in a computationally inexpensive manner.

Algorithms↗
PubMed2005

Functional, perfusion and diffusion MRI of acute focal ischemic brain injury.

Combined functional, perfusion and diffusion magnetic resonance imaging (MRI) with a temporal resolution of 30 mins was performed on permanent and transient focal ischemic brain injury in rats during the acute phase. The apparent diffusion coefficient (ADC), baseline cerebral blood flow (CBF), and functional MRI (fMRI) blood-oxygen-level-dependent (BOLD), CBF, and CMRO(2) responses associated with CO(2) challenge and forepaw stimulation were measured. An automated cluster analysis of ADC and CBF data was used to track the spatial and temporal progression of different tissue types (e.g., normal, 'at risk,' and ischemic core) on a pixel-by-pixel basis. With permanent ischemia (n=11), forepaw stimulation fMRI response in the primary somatosensory cortices was lost, although vascular coupling (CO(2) response) was intact in some animals. Control experiments in which the right common carotid artery was ligated without causing a stroke (n=8) showed that the delayed transit time had negligible effect on the fMRI responses in the primary somatosensory cortices. With temporary (15-mins, n=8) ischemia, transient CBF and/or ADC declines were observed after reperfusion. However, no T(2) or TTC lesions were observed at 24 h except in two animals, which showed very small subcortical lesions. Vascular coupling and forepaw fMRI response also remained intact. Finally, comparison of the relative and absolute fMRI signal changes suggest caution when interpreting percent changes in disease states in which the baseline signals are physiologically altered; quantitative CBF fMRI are more appropriate measures. This approach provides valuable information regarding ischemic tissue viability, vascular coupling, and functional integrity associated with ischemic injury and could have potential clinical applications.

Animals↗
PubMed2005

Thrombolytic therapy for acute ischemic stroke: 3 h and beyond.

The current status of thrombolytic therapy approved by the US Food and Drug Administration is intravenous recombinant plasminogen activator given within 3 h of the onset of ischemic stroke. Intra-arterial therapy is possible for up to 6 h but is not Food and Drug Administration-approved for this purpose. Based on current radiologic methods (i.e., magnetic resonance imaging and perfusion computed tomography scans), it is being increasingly realized that the time window for effective thrombolytic therapy is variable, and salvageable tissue in the form of the ischemic penumbra may exist for longer periods of time and could therefore offer a greater time window based on these imaging studies. Development of an effective neuroprotective drug would greatly enhance the stability of the penumbra and offer further opportunities for extending the time window for reperfusion.

Acute Disease↗
PubMed2004

Complications and pitfalls in rat stroke models for middle cerebral artery occlusion: a comparison between the suture and the macrosphere model using magnetic resonance angiography.

BACKGROUND AND PURPOSE: Investigating focal cerebral ischemia requires animal models that are relevant to human stroke. Complications and side effects are common among these models. The present study describes potential pitfalls in 3 techniques for middle cerebral artery occlusion (MCAO) in rats using magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). METHODS: Rats were subjected to temporary MCAO for 90 minutes using the suture technique (group I; n=10) or to permanent MCAO using the suture technique (group II; n=10) or the macrosphere technique (group III; n=10). Clinical evaluation was performed after 3 hours and 24 hours. After 24 hours, animals underwent MRI and MRA to determine lesion size and the intracranial vascular status. RESULTS: Hemispheric lesion volume was significantly smaller in group I (14.6%) compared with groups II (35.2%; P<0.01) and III (21.3%; P<0.05). Two animals (1 each in group II and III) did not demonstrate neurological deficits and had no lesion on MRI and a patent MCA main stem on MRA. Subarachnoid hemorrhage was detected in 2 animals (1 each in group I and II). MRA indicated a patent MCA main stem in 2 animals (group II), although both rats displayed neurological deficits. Hypothalamic infarction with subsequent pathological hyperthermia was detected in all animals in group II and in 1 rat in group III. CONCLUSIONS: Model failures occurred frequently in all groups. MRI and MRA helps to identify animals that need to be excluded from experimental stroke studies.

Animals↗
PubMed2004

Characterizing the diffusion/perfusion mismatch in experimental focal cerebral ischemia.

Diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) can rapidly detect lesions in acute ischemic stroke patients. The PWI volume is typically substantially larger than the DWI volume shortly after onset, that is, a diffusion/ perfusion mismatch. The aims of this study were to follow the evolution of the diffusion/ perfusion mismatch in permanent and 60- minute temporary focal experimental ischemia models in Sprague-Dawley rats using the intraluminal middle cerebral artery occlusion (MCAO) method. DWI and arterial spin-labeled PWI were performed at 30, 60, 90, 120, and 180 minutes after occlusion and lesion volumes (mm(3)) calculated At 24 hours after MCAO, and infarct volume was determined using triphenyltetrazolium chloride staining. In the permanent MCAO group, the lesion volume on the ADC maps was significantly smaller than that on the cerebral blood flow maps through the first 60 minutes after MCAO; but not after 90 minutes of occlusion. With 60 minutes of transient ischemia, the diffusion/perfusion mismatch was similar, but after reperfusion, the lesion volumes on ADC and cerebral blood flow maps became much smaller. There was a significant difference in 24- hour infarct volumes between the permanent and temporary occlusion groups.

Animals↗
PubMed2004

Microsphere-induced embolic stroke: an MRI study.

Despite the many studies of the middle cerebral artery occlusion (MCAO) model, efficient therapy for stroke is still lacking, emphasizing the need for further development and characterization of experimental stroke models. In the present study, the rather unexplored multifocal microsphere-induced stroke model in rats was characterized by multiparametric MRI. We induced microembolic infarction in a group of Sprague-Dawley rats by injecting a dose of about 1000 50-microm polyethylene microspheres intracranially from the external carotid artery. Diffusion-, perfusion-, and T(2)-weighted MRI were used to evaluate the infarct development during and following the first 3 hr after microsphere injection (N = 20). The animals were also imaged at 12-hr (N = 8), 24-hr (N = 17), and 48-hr (N = 5) time points. After the final imaging time point, the brains were removed and sectioned into 2-mm-thick slices, and infarct volumes were measured by 2,3,4-triphenyltetrazolium chloride (TTC) staining. From calculated apparent diffusion coefficient (ADC) maps, a volume of reduced ADC appeared 0.5-1.0 hr postinjection, and by the 3-hr time point the volume of ADC reduction had increased to a size of 5% +/- 1% (mean +/- SEM) of the brain hemisphere. The lesion volume increased significantly (P < 0.01) to 16% +/- 2% of the hemisphere volume at the 12-hr time point, while at 24 hr the lesion (15% +/- 2% of the hemisphere) was also significantly larger (P < 0.001) than at 3 hr. The perfusion deficit resulting from the microsphere injection was immediate, going from a cerebral blood flow index (CBF(i)) of 74% +/- 3% at the time of microsphere injection to 68% +/- 2% of the contralateral mean at 3 hr (P < 0.05), to 55% +/- 4% of the contralateral values at 12 hr (P < 0.05), and to 57% +/- 2% of the contralateral mean at 24 hr (P < 0.001). The lesion development in the microsphere-induced stroke model was found to be slower than in the MCAO model, and continued up to the 24-48-hr time point.

Animals↗
PubMed2004

Partial-volume effect on ischemic tissue-fate delineation using quantitative perfusion and diffusion imaging on a rat stroke model.

Partial-volume effects (PVE) in stroke imaging could hinder proper delineation of normal, ischemic, and at-risk tissues. Cerebral-blood-flow (CBF) and apparent diffusion coefficient (ADC) were measured at high and low resolution (HR = 128 x 128, LR = 64 x 64) in focal ischemia in rats during the acute phase. The data were evaluated for PVE on ischemic tissue classification on a pixel-by-pixel basis and the misclassified pixels were quantified as ischemia progressed. The main drawbacks of high-resolution imaging are reduced temporal resolution and/or signal-to-noise ratio. The high- versus low-resolution scatterplots and histograms of pixels along the normal-abnormal boundaries in the ADC and CBF maps showed marked ischemia-related PVE. By comparison with the homologous regions in the contralateral normal hemisphere, the effect of increased noise and intrinsic tissue heterogeneity due to high resolution could be distinguished from ischemia-related PVE. Degrading the high-resolution (128 x 128) data to a 64 x 64 or 32 x 32 matrix increased the severity of PVE. Zero-filling of low-resolution (64 x 64) data to 128 x 128 also increased PVE. It was concluded that PVE: (1) misclassified substantial pixels along the normal-abnormal boundaries, (2) overestimated abnormal volumes at the expense of mostly "at-risk" and some "normal" tissues, (3) were more severe at the early time points postischemia, and (4) confounded the interpretation of the operationally defined ischemic penumbra.

Animals↗
PubMed2004

Applications of diffusion/perfusion magnetic resonance imaging in experimental and clinical aspects of stroke.

The acute evaluation of stroke patients has undergone dramatic advances in the recent past. The increasing availability of novel magnetic resonance imaging (MRI) techniques, such as diffusion and perfusion MRI, provides a plethora of information to clinicians evaluating patients suspected of having an acute stroke. This review focuses on recent advances with experimental and clinical applications of perfusion and diffusion imaging and their utility in identifying potentially salvageable ischemic tissue in rat stroke model and stroke patients.

Animals↗
PubMed2004

Middle cerebral artery occlusion during MR-imaging: investigation of the hyperacute phase of stroke using a new in-bore occlusion model in rats.

Magnetic resonance imaging (MRI) provides insights into the dynamics of focal cerebral ischemia. Usually, experimental stroke is induced outside the magnet bore, preventing investigators from acquiring pre-ischemic images for later pixel-by-pixel comparisons and from studying the earliest changes in the hyperacute phase of ischemia. Herein, we introduce a new and easy to apply in-bore occlusion protocol based on the intraarterial embolization of ceramic macrospheres. PE-50 tubing, filled with saline and six macrospheres (0.315-0.355 mm in diameter), was placed into the internal carotid artery (ICA) of anesthetized Sprague-Dawley rats. The animals were transferred into an MRI scanner (7.0 T) and baseline diffusion-weighted imaging (DWI) and T2-imaging was performed. Then the macrospheres were injected into the internal artery to occlude the MCA. Post-ischemic DWI and T2-imaging was started immediately thereafter. The apparent diffusion coefficient (ADC) (a marker for cytotoxic brain edema) and T2-relaxation time (a marker for vasogenic brain edema) were determined in the ischemic lesions and compared to the unaffected hemisphere. ADC significantly declined within the first 5-10 min after stroke onset. T2-relaxation time increased as early as at the first T2-imaging time-point (20-35 min after embolization). After 150 min of ischemia, the lesions covered 18.0 +/- 7.4% of the hemispheres. The model failed in one out of nine animals (11%). This model allows MR-imaging from the initial minutes after permanent middle cerebral artery (MCA) occlusion. It does not permit reperfusion. This technique might provide information about the pathophysiological processes in the hyperacute phase of stroke.

Acute Disease↗