MR vascular fingerprinting: A new approach to compute cerebral blood volume, mean vessel radius, and oxygenation maps in the human brain.

In the present study, we describe a fingerprinting approach to analyze the time evolution of the MR signal and retrieve quantitative information about the microvascular network. We used a Gradient Echo Sampling of the Free Induction Decay and Spin Echo (GESFIDE) sequence and defined a fingerprint as the ratio of signals acquired pre- and post-injection of an iron-based contrast agent. We then simulated the same experiment with an advanced numerical tool that takes a virtual voxel containing blood vessels as input, then computes microscopic magnetic fields and water diffusion effects, and eventually derives the expected MR signal evolution. The parameter inputs of the simulations (cerebral blood volume [CBV], mean vessel radius [R], and blood oxygen saturation [SO2]) were varied to obtain a dictionary of all possible signal evolutions. The best fit between the observed fingerprint and the dictionary was then determined by using least square minimization. This approach was evaluated in 5 normal subjects and the results were compared to those obtained by using more conventional MR methods, steady-state contrast imaging for CBV and R and a global measure of oxygenation obtained from the superior sagittal sinus for SO2. The fingerprinting method enabled the creation of high-resolution parametric maps of the microvascular network showing expected contrast and fine details. Numerical values in gray matter (CBV=3.1±0.7%, R=12.6±2.4µm, SO2=59.5±4.7%) are consistent with literature reports and correlated with conventional MR approaches. SO2 values in white matter (53.0±4.0%) were slightly lower than expected. Numerous improvements can easily be made and the method should be useful to study brain pathologies.

MRI guides diagnostic approach for ischaemic stroke.

BACKGROUND AND AIM: Identification of ischaemic stroke subtype currently relies on clinical evaluation supported by various diagnostic studies. The authors sought to determine whether specific diffusion-weighted MRI (DWI) patterns could reliably guide the subsequent work-up for patients presenting with acute ischaemic stroke symptoms. METHODS: 273 consecutive patients with acute ischaemic stroke symptoms were enrolled in this prospective, observational, single-centre NIH-sponsored study. Electrocardiogram, non-contrast head CT, brain MRI, head and neck magnetic resonance angiography (MRA) and transoesophageal echocardiography were performed in this prespecified order. Stroke neurologists determined TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification on admission and on discharge. Initial TOAST stroke subtypes were compared with the final TOAST subtype. If the final subtype differed from the initial assessment, the diagnostic test deemed the principal determinant of change was recorded. These principal determinants of change were compared between a CT-based and an MRI-based classification schema. RESULTS: Among patients with a thromboembolic DWI pattern, transoesophageal echocardiography was the principal determinant of diagnostic change in 8.8% versus 0% for the small vessel group and 1.7% for the other group (p<0.01). Among patients with the combination of a thromboembolic pattern on MRI and a negative cervical MRA, transoesophageal echocardiography led to a change in diagnosis in 12.1%. There was no significant difference between groups using a CT-based scheme. CONCLUSIONS: DWI patterns appear to predict stroke aetiologies better than conventional methods. The study data suggest an MRI-based diagnostic algorithm that can potentially obviate the need for echocardiography in one-third of stroke patients and may limit the number of secondary extracranial vascular imaging studies to approximately 10%.

Chan chan: andean alternative of the preindustrial city.

I have discussed Chan Chan in terms of its political and economic characteristics because state organization had a pervasive impact on the growth and structure of the settlement. In this sense the capital of Chimor resembles Cuzco the Inca capital (1). Both metropolitan centers served as seats of Andean empires governed by noble classes headed by members of royal dynasties. Each state relied on a system of labor taxation and controlled the production, collection, and redistribution of goods. These political and economic institutions gave the sites distinctive but parallel forms. First, the settlements were large, containing a great deal of monumental architecture, but size and construction do not reflect substantial populations because building was done by nonresident work forces. Second, the urban proletariat were relatively few in numbers and composed of retainers or service personnel at Cuzco, as well as craftsmen and artisans at Chan Chan. Third, civic facilities were intended to serve the aristocracy and the state, not the common citizenry because these were governmental, not folk or popular, centers. And, fourth, palaces tied up a great amount of urban space because each monarch built his own seat of government during life and this became a monument to his name after death. In conclusion, I cannot say Chan Chan and Cuzco are necessarily typical of other prehistoric population centers in the region because these centers are little studied. I can, however, say Chan Chan was distinct from the preindustrial cities of Europe and Mesopotamia, but this is not surprising because the capital of Chimor was the product of distinctly Andean cultural institutions.

Cotton remains from archeological sites in central coastal peru.

Cotton remains from four archeological sites in central coastal Peru, representing a time sequence from about 2500 to 1000 B.C., were compared with similar materials obtained from living wild and cultivated forms of Gossypium barbadense L. The comparison revealed that the archeological cotton samples were primitive forms of Gossypium barbadense, differing little from present-day wild forms of the same species. Although not the earliest cottons recorded for the New World, they appear to represent the earliest stages of cotton domestication yet recorded.

Microstructure of temporo-parietal white matter as a basis for reading ability: evidence from diffusion tensor magnetic resonance imaging.

Diffusion tensor magnetic resonance imaging (MRI) was used to study the microstructural integrity of white matter in adults with poor or normal reading ability. Subjects with reading difficulty exhibited decreased diffusion anisotropy bilaterally in temporoparietal white matter. Axons in these regions were predominantly anterior-posterior in direction. No differences in T1-weighted MRI signal were found between poor readers and control subjects, demonstrating specificity of the group difference to the microstructural characteristics measured by diffusion tensor imaging (DTI). White matter diffusion anisotropy in the temporo-parietal region of the left hemisphere was significantly correlated with reading scores within the reading-impaired adults and within the control group. The anisotropy reflects microstructure of white matter tracts, which may contribute to reading ability by determining the strength of communication between cortical areas involved in visual, auditory, and language processing.

Brain Diffusion Abnormalities in Children with Tension-Type and Migraine-Type Headaches.

BACKGROUND AND PURPOSE: Tension-type and migraine-type headaches are the most common chronic paroxysmal disorders of childhood. The goal of this study was to compare regional cerebral volumes and diffusion in tension-type and migraine-type headaches against published controls. MATERIALS AND METHODS: Patients evaluated for tension-type or migraine-type headache without aura from May 2014 to July 2016 in a single center were retrospectively reviewed. Thirty-two patients with tension-type headache and 23 with migraine-type headache at an average of 4 months after diagnosis were enrolled. All patients underwent DWI at 3T before the start of pharmacotherapy. Using atlas-based DWI analysis, we determined regional volumetric and diffusion properties in the cerebral cortex, thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens, brain stem, and cerebral white matter. Multivariate analysis of covariance was used to test for differences between controls and patients with tension-type and migraine-type headaches. RESULTS: There were no significant differences in regional brain volumes between the groups. Patients with tension-type and migraine-type headaches showed significantly increased ADC in the hippocampus and brain stem compared with controls. Additionally, only patients with migraine-type headache showed significantly increased ADC in the thalamus and a trend toward increased ADC in the amygdala compared with controls. CONCLUSIONS: This study identifies early cerebral diffusion changes in patients with tension-type and migraine-type headaches compared with controls. The hypothesized mechanisms of nociception in migraine-type and tension-type headaches may explain the findings as a precursor to structural changes seen in adult patients with chronic headache.

Contrast-enhanced magnetic resonance imaging of tumor-bearing mice treated with human recombinant tumor necrosis factor alpha.

Pharmacological effects of recombinant human tumor necrosis factor alpha (TNF) were studied in a mouse fibrosarcoma model using magnetic resonance imaging enhanced with a macromolecular contrast agent, albumin(gadolinium-diethylenetriamine pentaacetic acid)35. TNF was administered i.v. in a dose of 150 micrograms/kg, 60 to 80 min prior to imaging. Contrast-enhanced and nonenhanced magnetic resonance images of TNF-treated (n = 10) and untreated (n = 8) Meth A fibrosarcomas were obtained at 2.0 Tesla using T1-weighted spin-echo pulse sequences. Serial images spanning an interval of 60 to 120 min after TNF administration showed that the TNF-treated tumors enhanced significantly more overall than did untreated tumors (43% versus 31%). The most marked differential tumor enhancement was observed in the tumor rim (59% versus 40%). Nontumorous tissue, including muscle and brain, revealed no significant enhancement differences between TNF-treated animals and controls. The observed tumor enhancement corresponded strongly with Evans blue staining; the TNF-treated tumors stained deep blue, while untreated tumors and normal tissues observed did not stain. The different enhancement and Evans blue staining patterns between TNF-treated tumors and untreated tumors are attributed to TNF-induced changes in tumor capillary integrity. The data indicate that TNF effects on tumors include an increased capillary permeability for macromolecules at early times after administration. The ability to detect changes in capillary permeability in vivo using contrast-enhanced magnetic resonance imaging may prove to be clinically useful to monitor tumor response to TNF.

Early life stress and inherited variation in monkey hippocampal volumes.

BACKGROUND: Opportunities for research on the causes and consequences of stress-related hippocampal atrophy are limited in human psychiatric disorders. Therefore, this longitudinal study investigated early life stress and inherited variation in monkey hippocampal volumes. METHODS: Paternal half-siblings raised apart from one another by different mothers in the absence of fathers were randomized to 1 of 3 postnatal conditions that disrupted diverse aspects of early maternal care (n = 13 monkeys per condition). These conditions were previously shown to produce differences in social behavior, emotional reactivity, and neuroendocrine stress physiology. Hippocampal volumes were subsequently determined in adulthood by high-resolution magnetic resonance imaging. RESULTS: Adult hippocampal volumes did not differ with respect to the stressful postnatal conditions. Based on paternal half-sibling effects, the estimated proportion of genetic variance, ie, heritability, was 54% for hippocampal size. Paternal half-siblings with small adult hippocampal volumes responded to the removal of all mothers after weaning with initially larger relative increases in cortisol levels. Plasma cortisol levels 3 and 7 days later, and measures of cortisol-negative feedback in adulthood were not, however, correlated with hippocampal size. CONCLUSIONS: In humans with mood and anxiety disorders, small hippocampal volumes have been taken as evidence that excessive stress levels of cortisol induce hippocampal volume loss. Results from this study of monkeys suggest that small hippocampi also reflect an inherited characteristic of the brain. Genetically informed clinical studies should assess whether inherited variation in hippocampal morphology contributes to excessive stress levels of cortisol through diminished neuroendocrine regulation.

Relationship between apparent diffusion coefficient and subsequent hemorrhagic transformation following acute ischemic stroke.

BACKGROUND AND PURPOSE: A method for identifying patients at increased risk for developing secondary hemorrhagic transformation (HT) after acute ischemic stroke could be of significant value, particularly in patients being considered for thrombolytic therapy. We hypothesized that diffusion-weighted MRI might aid in the identification of such patients. METHODS: We retrospectively analyzed 17 patients with ischemic stroke who received diffusion-weighted MRI within 8 hours of symptom onset and who also received follow-up neuroimaging within 1 week of initial scan. The apparent diffusion coefficient (ADC) for each pixel in the whole ischemic area was calculated, generating a histogram of values. Areas subsequently experiencing HT were then compared with areas not experiencing HT to determine the relationship between ADC and subsequent HT. RESULTS: A significantly greater percentage of pixels possessed lower ADCs (40% of the pixels possessed values

Reversal of early diffusion-weighted magnetic resonance imaging abnormalities does not necessarily reflect tissue salvage in experimental cerebral ischemia.

BACKGROUND AND PURPOSE: Diffusion-weighted MRI (DWI) can detect early ischemic changes and is sometimes used as a surrogate neurological end point in clinical trials. Recent experimental stroke studies have shown that with brief periods of ischemia, some DWI lesions transiently reverse, only to recur later. This study examined the histological condition of the tissue during the period of DWI reversal. METHODS: Rats underwent 30 minutes of middle cerebral artery occlusion followed by reperfusion. DWI images were obtained during ischemia and 3 to 5 hours, 1 day, and 7 days later. MRI scans were compared with histology (5 hours, n=5; 7 days, n=5) with the use of neuronal (microtubule-associated protein 2 [MAP2]) and astrocytic (glial fibrillary acidic protein [GFAP]) markers and heat-shock protein 72 (HSP72). RESULTS: DWI abnormalities reversed 3 to 5 hours after ischemia onset but recurred at 1 day. Four animals showed complete reversal of the initial DWI hyperintensity, and 6 showed partial reversal. When the 5-hour DWI was completely normal, there was significant loss of MAP2 immunoreactivity, comprising approximately 30% of the initial DWI lesion. However, GFAP staining revealed morphologically normal astrocytes. HSP72 immunoreactivity at 5 hours was extensive and corresponded to the initial DWI lesion. CONCLUSIONS: After brief ischemic periods, normalization of the DWI does not necessarily imply that the tissue is normal. Neurons already exhibit evidence of structural damage and stress. Normal GFAP staining suggests that other nonneuronal cell populations may partially compensate for altered fluid balances at the time of DWI reversal despite the presence of neuronal injury. These observations suggest that caution is warranted when relying solely on DWI for assessment of ischemic damage.

Is early ischemic lesion volume on diffusion-weighted imaging an independent predictor of stroke outcome? A multivariable analysis.

BACKGROUND AND PURPOSE: The heterogeneity of stroke makes outcome prediction difficult. Neuroimaging parameters may improve the predictive value of clinical measures such as the National Institutes of Health Stroke Scale (NIHSS). We investigated whether the volume of early ischemic brain lesions assessed with diffusion-weighted imaging (DWI) was an independent predictor of functional outcome. METHODS: We retrospectively selected patients with nonlacunar ischemic stroke in the anterior circulation from 4 prospective Stanford Stroke Center studies evaluating early MRI. The baseline NIHSS score and ischemic stroke risk factors were assessed. A DWI MRI was performed within 48 hours of symptom onset. Clinical characteristics and early lesion volume on DWI were compared between patients with an independent outcome (Barthel Index score >/=85) and a dependent outcome (Barthel Index score <85) at 1 month. A logistic regression model was performed with factors that were significantly different between the 2 groups in univariate analysis. RESULTS: Sixty-three patients fulfilled the entry criteria. One month after symptom onset, 24 patients had a Barthel Index score <85 and 39 had a Barthel Index score >/=85. In univariate analysis, patients with independent outcome were younger, had lower baseline NIHSS scores, and had smaller lesion volumes on DWI. In a logistic regression model, DWI volume was an independent predictor of outcome, together with age and NIHSS score, after correction for imbalances in the delay between symptom onset and MRI. CONCLUSIONS: DWI lesion volume measured within 48 hours of symptom onset is an independent risk factor for functional independence. This finding could have implications for the design of acute stroke trials.

High speed diffusion magnetic resonance imaging of ischemia and spontaneous periinfarct spreading depression after thromboembolic stroke in the rat.

Spontaneous episodes of transient cell membrane depolarization (spreading depression [SD]) occur in the surroundings of experimental stroke lesions and are believed to contribute to infarct growth. Diffusion-weighted imaging (DWI) is capable of detecting the water shifts from extracellular to intracellular space associated with SD waves and ischemia, and can make in vivo measurements of these two features on a pixel-by-pixel basis with good temporal resolution. Using continuous high speed DWI with a temporal resolution of 12 seconds over a period of 3 hours, the in vivo contribution of spontaneous SDs to the development of ischemic tissue injury was examined in 8 rats using a thromboembolic stroke model. During the observation period, the initial lesion volume increased in 4 animals, remained unchanged in 1 animal, and decreased in 3 animals (most likely because of spontaneous clot lysis). Irrespective of the lesion evolution patterns, animals demonstrated 6.5 +/- 2.1 spontaneous SDs outside of the ischemic core. A time-to-peak analysis of apparent diffusion coefficient (ADC) changes for each SD wave demonstrated multidirectional propagation patterns from variable initiation sites. Maps of the time constants of ADC recovery, reflecting the local energy supply and cerebral blood flow, revealed prolonged recovery times in areas close to the ischemic core. However, repetitive SD episodes in the periinfarct tissue did not eventually lead to permanent ADC reductions. These results suggest that spontaneous SD waves do not necessarily contribute to the expansion of the ischemic lesion volume in this model.

High-speed MR imaging of ischemic brain injury following stenosis of the middle cerebral artery.

Magnetic susceptibility contrast-enhanced and diffusion-weighted echo planar magnetic resonance (MR) imaging was performed using a cat model of acute regional cerebral ischemia induced by partial stenosis of the right middle cerebral artery (MCA). The imaging data were correlated with triphenyltetrazolium chloride (TTC)-stained histopathologic coronal brain sections to determine the prognostic efficacy of high-speed MR imaging techniques in differentiating mild, moderate, and severe cerebral hypoperfusion. Brains of animals without cortical injury on TTC staining were found to have a reduction in peak contrast enhancement of 32 +/- 6% (mean +/- SD) below control values with no significant change in the apparent diffusion coefficient (ADC), determined from the diffusion-weighted MR images. In cases where moderate ischemic injury was observed in the TTC-stained sections, a 10-20% drop in the ADC was found over the 6-h study period, accompanied by a much wider variation in peak contrast enhancement. Finally, where TTC staining showed severe ischemic brain damage, a 40-50% drop in ADC and a reduction in peak contrast enhancement effect of > 95% were observed as early as 1 h following MCA stenosis. The significant correlation between imaging observations and histologically confirmed cerebral ischemia indicates that magnetic susceptibility contrast-enhanced echo planar MR imaging is sensitive to slight reductions in cerebral perfusion that fall below the threshold for reliably detectable ischemia-induced alterations in ADC. First-pass perfusion-sensitive imaging may thus be diagnostically useful in differentiating severely hypoperfused permanently injured tissue from the mildly hypoperfused ischemic penumbra.

Experimental cerebral venous thrombosis: evaluation using magnetic resonance imaging.

Diffusion-weighted (DWI), dynamic contrast-enhanced (perfusion imaging), and conventional spin-echo magnetic resonance imaging (MRI) were applied to characterize the pathophysiology of cerebral venous thrombosis (CVT) in the rat. We induced CVT by rostral and caudal ligation of the superior sagittal sinus (SSS) and injection of a thrombogenic cephalin suspension. The resulting pathology was monitored in an acute and long-term study group. Evans blue and hematoxylin-eosin staining was performed for comparison with MRI data. A subgroup of animals was treated with i.v. tissue plasminogen activator (t-PA). Successful thrombosis of the SSS was confirmed by macropathology or histopathology in all rats. Parenchymal lesions as shown by MRI, however, were present only in animals with additional involvement of cortical cerebral veins (11 of 18 rats). The early pathology was clearly detected with the DWI. The apparent diffusion coefficient declined to 56 +/- 7% of control value at 0.5 h and slowly increased to 84 +/- 8% by 48 h. Perfusion imaging showed parasagittal perfusion deficits. Treatment with t-PA partially resolved the hyperintensity on DWI. Evidence of blood-brain-barrier disruption was observed 2 to 3 h after induction of CVT. In conclusion, experimental CVT is characterized by early cytotoxic edema closely followed by vasogenic edema. The t-PA treatment partially reversed the DWI signal changes consistent with regional tissue recovery, as shown by histopathology. These results encourage the use of cytoprotective drugs in addition to anticoagulant or thrombolytic therapy.

Magnetic resonance imaging assessment of cerebral hemodynamics during spreading depression in rats.

High-speed magnetic resonance imaging was used to perform simultaneous measurements of relative cerebral blood volume (rCBV) and water diffusion changes during spreading depression (SD) induced by cortical potassium chloride application. Rats were fitted epidurally with a rubber chamber. Potassium chloride was perfused through the chamber until SD was indicated by a negative direct current (DC) potential shift. Magnetic resonance imaging scans used echo planar diffusion and T2-weighted images. Iron dextran was injected as a blood pool contrast agent to make subsequent changes in T2 (or T2*) directly proportional to changes in CBV. Multislice maps of apparent diffusion coefficient (ADC) and rCBV were generated with 6- to 16-second time resolution, which revealed transient ADC and rCBV changes propagating over the cortex after potassium chloride application. Transient ADC declines appeared simultaneously with the DC shift, whereas rCBV increase followed with a delay of 16.4+/-14.9 seconds. Prolonged rCBV decrease was observed after the initial increase during the SD in half of the animals. The delayed rCBV response after the ADC change supports the observation of increased energy demand because of repolarization. Simultaneous DC potential recording and ADC measurements in corresponding sites of the cortex indicate that transient ADC decreases during SD reflect water shifts associated with cell depolarization.

Polynitroxyl albumin reduces infarct size in transient focal cerebral ischemia in the rat: potential mechanisms studied by magnetic resonance imaging.

Nitroxide free radicals are known to protect cells from oxidative damage. Diffusion-weighted and perfusion-weighted magnetic resonance imaging was used to evaluate the effects of polynitroxyl albumin (PNA) in a middle cerebral artery intraluminal suture model of transient focal cerebral ischemia in the rat. Three groups of Sprague-Dawley rats were investigated: (1) PNA (N=6), (2) human serum albumin (N =6), and (3) saline (N=7). The middle cerebral artery was occluded for 2 hours. Treatment was started 30 minutes after induction of ischemia. A total dose of 1% body weight (volume/weight) of PNA (23.5 mg/dL protein and 110 mmol/L nitroxide), albumin (23.5 mg/dL), or saline was injected intravenously at three time points: 0.5% at 0.5 hours, 0.25% at 2 hours (i.e., just before reperfusion), and 0.25% at 4 hours after occlusion. Six sets of diffusion- and perfusion-weighted magnetic resonance images were acquired throughout the 2 hours of ischemia and the 2 hours of reperfusion. The rats were killed at 24 hours, and the brains were stained with 2,3,5-triphenyltetrazolium chloride (TTC). Diffusion-weighted imaging showed that the growth of the ischemic lesion was suppressed in the PNA-treated group. The 4 hours diffusion-weighted imaging--derived hemispheric lesion volume in the PNA-treated group (25%+/-9%) was significantly smaller than that in the saline-treated (43%+/-13%; P=0.016) or albumin-treated groups (38%+/-6%; P=0.017). A larger difference was observed for the 24-hour TTC-derived lesion volumes in the PNA (8%+/-7%), saline (35%+/-8%; P < 0.001), and albumin (31%+/-6%; P < 0.001) groups. Perfusion-weighted imaging demonstrated a marked improvement in cerebral perfusion in the PNA-treated group during ischemia and reperfusion. In conclusion, treatment with PNA results in an improvement in perfusion and a reduction of infarct volume in a model of transient focal cerebral ischemia in the rat.

Gender differences in cerebral blood flow and oxygenation response during focal physiologic neural activity.

Using functional magnetic resonance imaging techniques CBF and oxygenation changes were measured during sustained checkerboard stimulation in 38 right-handed healthy volunteers (18 men and 20 women). The average blood oxygenation level dependent (BOLD) contrast technique signal intensity change was 1.67 +/- 0.6% in the group of male volunteers and 2.15 +/- 0.6% in the group of female volunteers (P < .05). Baseline regional CBF (rCBF) values in activated gray matter areas within the visual cortex were 57 +/- 10 mL x 100 g(-1) x min(-1) in women and 50 +/- 12 mL x 100 g(-1) x min(-1) in men, respectively (P = .09). Despite a broad overlap between both groups the rCBF increase was significantly higher in women compared to men (33 +/- 5 mL x 100 g(-1) x min(-1) versus 28 +/- 4 mL x 100 g(-1) x min(-1), P < .01). The increase of rCBF was not correlated with the baseline rCBF (mL x 100 g(-1) x min(-1)) (r(s) = 0.01, P = .9). Moreover, changes of rCBF were not correlated with changes in BOLD signal intensities (r(s) = 0.1, P = .7). Enhanced rCBF response in women during visual stimulation could be related to gender differences in visual physiology or may reflect gender differences in the vascular response to focal neuronal activation. Gender differences must be considered when interpreting the results of functional magnetic resonance imaging studies.

The effect of hypoxia on traumatic head injury in rats: alterations in neurologic function, brain edema, and cerebral blood flow.

We evaluated the effects of early posttraumatic hypoxia on neurologic function, magnetic resonance images (MRI), brain tissue specific gravities, and cerebral blood flow (CBF) in head-injured rats. By itself, an hypoxic insult (PaO2 40 mm Hg for 30 min) had little effect on any measure of cerebral function. After temporal fluid-percussion impact injury, however, hypoxia significantly increased morbidity. Of rats subjected to impact (4.9 +/- 0.3 atm) plus hypoxia, 71% had motor weakness contralateral to the impact side 24 h after injury, while only 29% of rats subjected to impact alone had demonstrable weakness (p less than 0.05). Lesions observed on MR images 24 h after injury were restricted to the impact site in rats with impact injury alone, but extensive areas with longer T1 relaxation times were observed throughout the ipsilateral cortex in rats with impact injury and hypoxic insult. Brain tissue specific gravity measurements indicated that much more widespread and severe edema developed in rats with impact injury and hypoxia. [14C]Iodoantipyrine autoradiography performed 24 h after injury showed that there was extensive hypoperfusion of the entire ipsilateral cortex in rats with impact injury and hypoxia. These results show that large areas of impact-injured brain are extremely vulnerable to secondary insults that can irreparably damage neural tissue, and provide experimental evidence for the observed adverse effects of hypoxia on outcome after human head injury.

Improved perfusion with rt-PA and hirulog in a rabbit model of embolic stroke.

We conducted a study using diffusion-weighted (DWI) and perfusion-weighted (PWI) magnetic resonance imaging (MRI) to evaluate the efficacy of thrombolysis in an embolic stroke model with recombinant tissue plasminogen activator (rt-PA) and hirulog, a novel direct-acting antithrombin. DWI can identify areas of ischemia minutes from stroke onset, while PWI identifies regions of impaired blood flow. Right internal carotid arteries of 36 rabbits were embolized using aged heterologous thrombi. Baseline DWI and PWI scans were obtained to confirm successful embolization. Four animals with no observable DWI lesion on the initial scan were excluded; therefore, a total of 32 animals were randomized to one of three treatment groups: rt-PA (n = 11), rt-PA plus hirulog (n = 11), or placebo (n = 10). Treatment was begun 1 h after stroke induction. Intravenous doses were as follows: rt-PA, 5 mg/kg over 0.5 h with 20% of the total dose given as a bolus; hirulog, 1 mg/kg bolus followed by 5 mg/kg over 1 h. MRI was performed at 2, 3, and 5 h following embolization. Six hours after embolization, brains were harvested, examined for hemorrhage, then prepared for histologic analysis. The rt-PA decreased fibrinogen levels by 73%, and hirulog prolonged the aPTT to four times the control value. Posttreatment areas of diffusion abnormality and perfusion delay were expressed as a ratio of baseline values. Significantly improved perfusion was seen in the rt-PA plus hirulog group compared with placebo (normalized ratios of the perfusion delay areas were as follows: placebo, 1.58, 0.47-3.59; rt-PA, 1.12, 0.04-3.95; rt-PA and hirulog, 0.40, 0.02-1.08; p < 0.05). Comparison of diffusion abnormality ratios measured at 5 h showed trends favoring reduced lesion size in both groups given rt-PA (normalized ratios of diffusion abnormality areas were as follows: placebo, 3.69, 0.39-15.71; rt-PA, 2.57, 0.74-5.00; rt-PA and hirulog, 1.95, 0.33-6.80; p = 0.32). Significant cerebral hemorrhage was observed in one placebo, two rt-PA, and three rt-PA plus hirulog treated animals. One fatal systemic hemorrhage was observed in each of the rt-PA groups. We conclude that rt-PA plus hirulog improves cerebral perfusion but does not necessarily reduce cerebral injury. DWI and PWI are useful methods for monitoring thrombolysis.

Prediction of hemorrhagic transformation following acute stroke: role of diffusion- and perfusion-weighted magnetic resonance imaging.

BACKGROUND: Acute diffusion-weighted (DWI) and perfusion-weighted (PWI) magnetic resonance imaging (MRI) findings may correlate with secondary hemorrhagic transformation (HT) risk in patients with stroke. This information could be of value, particularly in individuals being considered for thrombolytic therapy. OBJECTIVE: To determine the relationship between DWI and PWI findings and the risk of secondary HT in patients with acute stroke. DESIGN: Retrospective case series. SETTING: Academic medical center. PATIENTS: Twenty-seven patients with acute stroke capable of being evaluated with DWI/PWI 8 hours or less after symptom onset. MAIN OUTCOME MEASURES: Apparent diffusion coefficient values, perfusion delay measurements, and subsequent MRI or computed tomographic scans detected HT. RESULTS: The mean +/- SD apparent diffusion coefficient of ischemic regions that experienced HT was significantly lower than the overall mean +/- SD apparent diffusion coefficient of all ischemic areas analyzed (0.510 +/- 0.140 x 10(-3) mm(2)/s vs 623 +/- 0.113 x 10(-3) mm(2)/s; P =.004). This difference remained significant when comparing the HT-destined ischemic areas with the non-HT-destined areas within the same ischemic lesion (P =.02). Patients receiving recombinant tissue-type plasminogen activator (rt-PA) experienced HT significantly earlier than patients not receiving rt-PA (P =.002). Moreover, a persistent perfusion deficit in the area of subsequent hemorrhage at 3 to 6 hours after the initial MRI scan was identified in significantly more patients who experienced HT than in those who did not (83% vs 30%; P =.03). CONCLUSION: Both DWI and PWI scans detect abnormalities that are associated with HT. These findings support a role for MRI in identifying patients who are at increased risk for secondary HT following acute ischemic stroke.