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Marc Fisher

Publications and source records attributed to Marc Fisher.

At least 19 recordsLinked to original sources
PubMed2007

Translational research in stroke: taking advances in the pathophysiology and treatment of stroke from the experimental setting to clinical trials.

Many advances have occurred regarding an increased understanding of the basic pathophysiology of ischemic brain injury that could lead to enhanced therapy for this disorder. Among the more important basic science advances are enhanced knowledge of the components of the ischemic cascade, the phenomenon of ischemic preconditioning, the potential relevance of hibernation, studies on gene expression in ischemic tissue, and imaging identification of the ischemic penumbra. The large number of unsuccessful prior clinical trials with a wide range of purported acute stroke therapies has provided many insights and lessons regarding how to perform better trials in the future. Translating these basic science and clinical trial design advances into effective and safe therapies will require increased interaction and cooperation between basic scientists and clinical researchers.

Animals↗
PubMed2006

Comparison between coated vs. uncoated suture middle cerebral artery occlusion in the rat as assessed by perfusion/diffusion weighted imaging.

Differences among models in the temporal evolution of ischemia after middle cerebral artery occlusion (MCAO) in rats may considerably influence the results of experimental treatment studies. Using diffusion and perfusion imaging, we compared the spatiotemporal evolution of ischemia in Sprague-Dawley rats after permanent MCAO (pMCAO) with different types of sutures. Male Sprague-Dawley rats were randomly assigned to pMCAO produced with either 4-0 silicone coated (n=8), or 3-0 uncoated monofilaments (n=8). Serial determination of quantitative cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) maps were performed up to 3 h after pMCAO. Lesion volumes were calculated by using previously validated thresholds and correlated with infarct volume corrected for edema defined by 2,3,5-triphenyltetrazolium chloride (TTC) staining at 24 h after MCAO. The ADC/CBF-defined mismatch volume in the 4-0 coated suture model was present significantly longer (up to 120 min) compared to the uncoated 3-0 suture model (30 min). The TTC-derived infarct volume was significantly larger in the coated model (290.3+/-32.8 mm(3)) relative to the uncoated model (252.3+/-34.6 mm(3)). This study demonstrates that the type of suture may significantly influence the spatiotemporal evolution of the ADC/CBF-mismatch as well as the final infarct volume. These inter-model variations must be taken into account when assessing new therapeutic approaches on ischemic lesion evolution in the rat MCAO model.

Animals↗
PubMed2006

Long-term changes of functional MRI-based brain function, behavioral status, and histopathology after transient focal cerebral ischemia in rats.

BACKGROUND AND PURPOSE: The relation between recovery of brain function and neurological status after clinical and experimental cerebral ischemia is incompletely characterized. We assessed the evolution of ischemic injury, behavioral status, and brain activity at acute to chronic periods after transient middle cerebral artery occlusion (tMCAO) in rats. METHODS: Male Sprague-Dawley rats were subjected to 20-minute tMCAO (n=10) or sham operation (n=10). Sensorimotor behavioral testing and multimodal (diffusion, perfusion, T2, and functional) MRI, as well as postmortem hematoxylin-eosin staining, were performed before and up to 21 days after tMCAO. MRI and histological parameters were evaluated in 5 regions of interest within the sensorimotor network. Diffusion, perfusion, and T2 lesion volumes were calculated according to previously established viability thresholds. RESULTS: Diffusion and perfusion lesions were present during occlusion but disappeared completely and permanently within 30 minutes after reperfusion, with no T2 lesions seen. Functional MRI and behavioral deficits did not normalize until 1 and 21 days after tMCAO, respectively. Histology demonstrated selective neuronal cell death at 7 and 21 days after reperfusion. CONCLUSIONS: Twenty-minute tMCAO produced distinct changes on multimodal MRI, histology, and behavioral parameters acutely and chronically. Normal findings on MRI after transient ischemia may not indicate normal tissue status, as behavioral and histological anomalies remain. Behavioral dysfunction persisting long after the recovery of MRI parameters may relate to the subtle neuronal damage seen on histology. Together, these results may help explain unremitting neurological deficits in stroke or transient ischemic attack patients with normal MRI findings.

Animals↗
PubMed2006

The ischemic penumbra: a new opportunity for neuroprotection.

The development of acute stroke therapies has yielded only limited success and many failures in multiple clinical trials. The target of acute stroke therapy is that portion of the ischemic region that is still potentially salvageable, i.e. the ischemic penumbra. Neuroprotective drugs have the potential to prevent a portion of the ischemic penumbra from evolving into infracted tissue and designing trials that target neuroprotective drugs at patients with persistent penumbra should enhance the likelihood of a positive outcome. Currently, diffusion and perfusion MRI has the potential to approximate the location and persistence of the ischemic penumbra and can be used in clinical trials to select appropriate patients for inclusion and to evaluate a meaningful treatment effect. Perfusion CT may also have similar capabilities. Use of these imaging modalities in clinical trials and ultimately in clinical practice will likely help in the development and utilization of novel neuroprotective drugs.

Animals↗
PubMed2006

Comparison of ischemic lesion evolution in embolic versus mechanical middle cerebral artery occlusion in Sprague Dawley rats using diffusion and perfusion imaging.

BACKGROUND AND PURPOSE: Differences among models in the temporal evolution of ischemia after middle cerebral artery occlusion (MCAO) in rats may considerably influence the results of experimental stroke research. Using diffusion and perfusion imaging, we compared the spatiotemporal evolution of ischemia in Sprague Dawley rats after permanent suture MCAO (sMCAO; n=8) and embolic MCAO (eMCAO; n=8). METHODS: Serial measurements of quantitative cerebral blood flow (CBF) and the apparent diffusion coefficient (ADC) were performed up to 180 minutes after MCAO. ADC and CBF values within 5 different brain regions were analyzed. ADC and CBF lesion volumes were calculated by using previously established viability thresholds and correlated with infarct volume defined by 2,3,5-triphenyltetrazolium chloride staining 24 hours after MCAO. RESULTS: Compared with sMCAO animals, the threshold-derived CBF lesion volume was significantly larger in eMCAO at all time points (P<0.01), remained relatively constant over time, and was highly correlated with the 2,3,5-triphenyltetrazolium chloride-defined infarct size. The ADC lesion volume did not differ between models at any time point. A diffusion/perfusion mismatch was present significantly longer in eMCAO animals (P<0.05), and these rats demonstrated larger absolute mismatch volumes that were statistically significant at 30, 60, and 90 minutes (P<0.05). In both models, CBF and ADC declines were highly correlated. CONCLUSIONS: This study demonstrated substantial differences in acute ischemic lesion evolution between the eMCAO and sMCAO models.

Animals↗
PubMed2006

Differential recovery of multimodal MRI and behavior after transient focal cerebral ischemia in rats.

The association between recovery of brain function and behavior after transient cerebral ischemia in animals and humans is incompletely characterized. Quantitative diffusion- (DWI), perfusion- (PWI), T(2)-weighted (T(2)WI), and functional magnetic resonance imaging (fMRI) were performed before, during, and up to 1 day after 20-mins transient middle cerebral artery occlusion (tMCAO; n=6) or sham operation (n=6) in male Sprague-Dawley rats. Viability thresholds were employed to calculate diffusion, perfusion, and T(2) lesion volumes. Region of interest analysis was used to evaluate structural and functional MR signal changes within the sensorimotor network, which were then related to corresponding behavioral measures. Post-mortem 2,3,5-triphenyltetrazolium chloride (TTC) staining was performed 24 h after ischemia. Transient middle cerebral artery occlusion produced lesions on DWI and PWI, which fully recovered by 30 mins after reperfusion. Ipsilesional fMRI responses to hypercapnia and forepaw stimulation were significantly impaired after ischemia and did not fully normalize until 3 and 24 h after tMCAO, respectively. No abnormalities were observed on imaging or TTC at 24 h despite significant behavioral dysfunctions including contralesional forelimb impairment and ipsilesional neglect. No MRI, behavioral, or TTC anomalies were observed in sham-operated rats. There were no significant correlations between MRI parameters, behavior, and TTC in either group. Together, these results suggest that normal findings on diffusion, perfusion, and T(2) imaging shortly after transient ischemia may not indicate normal tissue status as indicated by fMRI and behavior, which may help explain the persistence of neurologic deficits in patients with normal conventional MRI after cerebral ischemia.

Animals↗
PubMed2006

The proteasome inhibitor VELCADE reduces infarction in rat models of focal cerebral ischemia.

The potential neuroprotective effects of VELCADE were investigated in two different models of focal cerebral ischemia. For time-window assessment, male Wistar-Kyoto rats were treated with 0.2 mg/kg VELCADE at 1, 2, or 3 h after the induction of permanent middle cerebral artery occlusion (MCAO) using the suture occlusion method (experiment 1). To evaluate effects in a different model, male Sprague-Dawley rats received 0.2 mg/kg VELCADE after embolic MCAO (experiment 2). Infarct volume was calculated based on TTC-staining 24 h postischemia and whole blood proteasome activity was fluorometrically determined in both experiments at baseline, 1 and 24 h post-MCAO. In experiment 1, a dose of 0.2 mg/kg inhibited proteasome activity by 77% and infarct volume was reduced to 175.7+/-59.9 mm3 and 205.9+/-83.9 mm3 (1 and 2 h group, respectively; p<0.05) compared to 306.5+/-48.5 mm3 (control). Treatment at 3 h was not neuroprotective (293.0+/-40.1 mm3). After embolic MCAO, infarct volume was 167.5+/-90.7 mm3 (treatment group) and 398.9+/-141.3 mm3 (control; p=0.002). In conclusion, VELCADE treatment inhibited whole blood proteasome activity and achieved significant neuroprotection in two rat models of focal cerebral ischemia at various time points poststroke.

Animals↗
PubMed2006

Results of the management of atherothrombosis with clopidogrel in high-risk patients trial: implications for the neurologist.

The secondary prevention of ischemic stroke is aided by the use of antiplatelet therapy, and the predominant current choices are aspirin, aspirin plus extended-release dipyridamole, and clopidogrel. The potential utility of combining platelet antiaggregants with different mechanisms of action proved successful with aspirin plus extended-release dipyridamole, and this approach has been explored with the combination of clopidogrel and aspirin. In the Management of Atherothrombosis With Clopidogrel in High-Risk Patients trial, this combination was compared with clopidogrel alone for secondary prevention in patients with transient ischemic attack and stroke in a high-risk population with a high prevalence of other vascular risk factors. A nonsignificant trend for a reduction of the combined endpoint of ischemic stroke, myocardial infarction, vascular death, and rehospitalization was observed in the combination therapy group (P = .24). The frequency of serious, life-threatening bleeding adverse effects was almost doubled in the combination arm. Neurologists need to be aware of these results and avoid the use of clopidogrel plus aspirin in patients with stroke or transient ischemic attack until evidence that the combination is safe in this population is provided. Neurologists faced with patients who have had a stroke or transient ischemic attack and are receiving this combination of antiplatelet agents after coronary stenting should inform their cardiology colleagues of the reported bleeding risk, and they should encourage the use of the combination for as short a time period as possible after such coronary intervention.

Brain Ischemia↗
PubMed2006

Role of heparin and low-molecular-weight heparins in the management of acute ischemic stroke.

The numerous large-scale randomized clinical trials performed during the last decade on either unfractionated heparin, or low molecular weight heparin have not been able to demonstrate undisputed benefits in patients with acute ischemic stroke, compared with no treatment or aspirin. However, a large number of these trials, including the International Stroke Trial and Chinese Acute Stroke Trial, exhibit severe methodological limitations and need to be interpreted with caution. Knowledge of thromboembolism pathophysiology and clinical experience leads to the theory that heparins will prevent red thrombus formation, propagation and embolism. Heparins effectively prevent venous thrombosis and pulmonary embolism. More trials are needed to test heparins in patients whose cardiocerebrovascular lesions are better defined by newer neuroimaging techniques. The efficacy of heparins has not been adequately tested in patients with defined stroke subtypes and occlusive vascular lesions. Heparins should not be indiscriminately given to all patients with acute ischemic stroke. High-quality, randomized trials that adequately study heparin use in patients using modern technology for vascular lesions and stroke subtypes are lacking, and need to be performed.

Acute Disease↗
PubMed2005

Effect of the Glycine Antagonist Gavestinel on cerebral infarcts in acute stroke patients, a randomized placebo-controlled trial: The GAIN MRI Substudy.

BACKGROUND AND PURPOSE: Gavestinel, GV150526, is a selective antagonist at the glycine site of the N-methyl-D-aspartate receptor. The safety and efficacy of GV150526 were studied in two phase III randomized placebo-controlled clinical trials of acute ischemic stroke patients within 6 h from onset [The Glycine Antagonist in Neuroprotection (GAIN) International and GAIN Americas Trials]. A planned MRI substudy within these trials investigated the effect of gavestinel on infarct volume. METHODS: Patients enrolled in the GAIN trials at designated MRI substudy sites were eligible if they had a pretreatment acute cortical lesion on diffusion-weighted MRI of at least 1.5 cm diameter or 5 cm(3). Final lesion assessment was performed on T(2)-weighted MRI at month 3. Blinded image analysis was performed centrally. The primary hypothesis was that gavestinel would attenuate lesion growth from baseline relative to placebo. RESULTS: A total of 106 patients were eligible, 75 (34 gavestinel, 41 placebo) of whom had month 3 scans (primary analysis population). No effects of gavestinel on infarct volume were observed in the primary or other analyses. However, significant associations of lesion volume to clinical severity and outcomes were observed. Ischemic lesion volume decrease was predictive of substantial clinical improvement. CONCLUSION: Consistent with the clinical outcomes in the GAIN trials, no effects of gavestinel on ischemic infarction was observed. Concordance of results of the clinical outcome trials with those of this infarct volume substudy as well the associations of infarct volume to clinical outcomes further support the potential role of infarct volume as a marker of outcome in dose finding and proof of principle acute stroke trials.

Cerebral Infarction↗
PubMed2005

Differences in ischemic lesion evolution in different rat strains using diffusion and perfusion imaging.

BACKGROUND AND PURPOSE: Interstrain differences in the temporal evolution of ischemia after middle cerebral artery occlusion (MCAO) in rats may considerably influence the results of experimental stroke research. We investigated, in 2 commonly used rat strains (Sprague-Dawley [SD] and Wistar-Kyoto [WK]), the spatiotemporal evolution of ischemia after permanent suture MCAO using diffusion and perfusion imaging. METHODS: Serial measurements of quantitative cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) were performed up to 210 min after MCAO. Lesion volumes were calculated by using previously established viability thresholds and correlated with infarct volume defined by 2,3,5-triphenyltetrazolium chloride staining 24 hours after MCAO. RESULTS: While the ADC-derived lesion volume increased rapidly during the first 120 min after MCAO and essentially stopped growing after 3 hours in SD rats, ADC lesion in WK rats increased progressively during the entire 210-min period and was significantly smaller at all time points (P<0.05). The abnormal perfusion volume correlated highly with the TTC-defined infarct size in both groups. In WK rats, the abnormal perfusion volume was significantly larger than the abnormal diffusion volume up to 90 min after MCAO (P<0.001), whereas the diffusion/perfusion mismatch was significant (P<0.001) only at 45 min in SD rats. ADC-CBF scatterplots analysis revealed a slower and less robust ADC decline over time in WK rats in pixels with severe (<20% of normal) and moderate (21 to 40% of normal) CBF reduction. CONCLUSIONS: This study demonstrated substantial differences in acute ischemic lesion evolution between SD and WK rats. These interstrain variations must be taken into account when assessing new therapeutic approaches on ischemic lesion evolution in the rat MCAO model.

Animals↗