Mahmoud Ashkanian

MRI Detection of Early Blood-Brain Barrier Disruption Parenchymal Enhancement Predicts Focal Hemorrhagic Transformation After Thrombolysis

Background and Purpose— Blood-brain barrier disruption may be a predictor of hemorrhagic transformation (HT) in ischemic stroke. We hypothesize that parenchymal enhancement (PE) on postcontrast T1-weighted MRI predicts and localizes subsequent HT. Methods— In a prospective study, 33 tPA-treated stroke patients were imaged by perfusion-weighted imaging, T1 and FLAIR before thrombolytic therapy and after 2 and 24 hours. Results— Postcontrast T1 PE was found in 5 of 32 patients (16%) 2 hours post-thrombolysis. All 5 patients subsequently showed HT compared to 11 of 26 patients without PE (P=0.043, specificity 100%, sensitivity 31%), with exact anatomic colocation of PE and HT. Enhancement of cerebrospinal fluid on FLAIR was found in 4 other patients, 1 of which developed HT. Local reperfusion was found in 4 of 5 patients with PE, whereas reperfusion was found in all cases of cerebrospinal fluid hyperintensity. Conclusions— PE detected 2 hours after thrombolytic therapy predicts HT with high specificity. Contrast-enhanced MRI may provide a tool for studying HT and targeting future therapies to reduce risk of hemorrhagic complications.

Ischemic injury detected by diffusion imaging 11 minutes after stroke.

A 78‐year‐old woman suffered a stroke inside a magnetic resonance scanner while being imaged because of a brief transient ischemic attack 2 hours earlier. Diffusion‐weighted images obtained 11 minutes after stroke showed tissue injury not found on initial images. The data show early, abrupt diffusion changes in hypoperfused tissue, adding to our understanding of the progression of microstructural abnormalities in the hyperacute phase of stroke. Ann Neurol 2005;58:462–465

Brain energy metabolism and blood flow differences in healthy aging

Cerebral metabolic rate of oxygen consumption (CMRO 2 ), cerebral blood flow (CBF), and oxygen extraction fraction (OEF) are important indices of healthy aging of the brain. Although a frequent topic of study, changes of CBF and CMRO 2 during normal aging are still controversial, as some authors find decreases of both CBF and CMRO 2 but increased OEF, while others find no change, and yet other find divergent changes. In this reanalysis of previously published results from positron emission tomography of healthy volunteers, we determined CMRO 2 and CBF in 66 healthy volunteers aged 21 to 81 years. The magnitudes of CMRO 2 and CBF declined in large parts of the cerebral cortex, including association areas, but the primary motor and sensory areas were relatively spared. We found significant increases of OEF in frontal and parietal cortices, excluding primary motor and somatosensory regions, and in the temporal cortex. Because of the inverse relation between OEF and capillary oxygen tension, increased OEF can compromise oxygen delivery to neurons, with possible perturbation of energy turnover. The results establish a possible mechanism of progression from healthy to unhealthy brain aging, as the regions most affected by age are the areas that are most vulnerable to neurodegeneration.

Normalization in PET group comparison studies--the importance of a valid reference region.

INTRODUCTION In positron emission tomography (PET) studies of cerebral blood flow (CBF) and metabolism, the large interindividual variation commonly is minimized by normalization to the global mean prior to statistical analysis. This approach requires that no between-group or between-state differences exist in the normalization region. Given the variability typical of global CBF and the practical limit on sample size, small group differences in global mean easily elude detection, but still bias the comparison, with profound consequences for the physiological interpretation of the results. MATERIALS AND METHODS Quantitative [15O]H2O PET recordings of CBF were obtained in 45 healthy subjects (21-81 years) and 14 patients with hepatic encephalopathy (HE). With volume-of-interest (VOI) and voxel-based statistics, we conducted regression analyses of CBF as function of age in the healthy group, and compared the HE group to a subset of the controls. We compared absolute CBF values, and CBF normalized to the gray matter (GM) and white matter (WM) means. In additional simulation experiments, we manipulated the cortical values of 12 healthy subjects and compared these to unaltered control data. RESULTS In healthy aging, CBF was shown to be unchanged in WM and central regions. In contrast, with normalization to the GM mean, CBF displayed positive correlation with age in the central regions. Very similar artifactual increases were seen in the HE comparison and also in the simulation experiment. CONCLUSION Ratio normalization to the global mean readily elevates CBF in unchanged regions when a systematic between-group difference exists in gCBF, also when this difference is below the detection threshold. We suggest that the routine normalization to the global mean in earlier studies resulted in spurious interpretations of perturbed CBF. Normalization to central WM yields less biased results in aging and HE and could potentially serve as a normalization reference region in other disorders as well.

IMPROVEMENT OF BRAIN TISSUE OXYGENATION BY INHALATION OF CARBOGEN

Hyperoxic therapy for cerebral ischemia is suspected to reduce cerebral blood flow (CBF), due to the vasoconstrictive effect of oxygen on cerebral arterioles. We hypothesized that vasodilation predominates when 5% CO(2) is added to the inhaled oxygen (carbogen). Therefore, we used positron emission tomography (PET) to measure CBF and cerebral metabolic rate of oxygen (CMRO(2)) during inhalation of test gases (O(2), CO(2), carbogen and atmospheric air) in 10 healthy volunteers. Arterial blood gases were recorded during administration of each gas. The data were analyzed with volume-of-interest and voxel-based statistical methods. Inhalation of CO(2) or carbogen significantly increased global CBF, whereas pure oxygen decreased global CBF. The CMRO(2) generally remained unchanged, except in white matter during oxygen inhalation relative to condition of atmospheric air inhalation. The volume-of-interest results were confirmed by statistical cluster analysis. Oxygen and carbogen were equally potent in increasing oxygen saturation of arterial blood (Sa(O2)). The present data demonstrate that inhalation of carbogen increases both CBF and Sa(O2) in healthy adults. In conclusion we speculate that carbogen inhalation is sufficient for optimal oxygenation of healthy brain tissue, whereas carbogen induces concomitant increases of CBF and Sa(O2).

Carbogen inhalation increases oxygen transport to hypoperfused brain tissue in patients with occlusive carotid artery disease: Increased oxygen transport to hypoperfused brain

Hyperoxic therapy for cerebral ischemia reduces cerebral blood flow (CBF) principally from the vasoconstrictive effect of oxygen on cerebral arterioles. Based on a recent study in normal volunteers, we now claim that the vasodilatory effect of carbon dioxide predominates when 5% CO(2) is added to inhaled oxygen (the mixture known as carbogen). In the present study, we measured CBF by positron emission tomography (PET) during inhalation of test gases (O(2), carbogen, and atmospheric air) in healthy volunteers (n = 10) and in patients with occlusive carotid artery disease (n = 6). Statistical comparisons by an additive ANOVA model showed that carbogen significantly increased CBF by 7.51 + or - 1.62 ml/100 g/min while oxygen tended to reduce it by -3.22 + or - 1.62 ml/100 g/min. A separate analysis of the hemisphere contralateral to the hypoperfused hemisphere showed that carbogen significantly increased CBF by 8.90 + or - 2.81 ml/100 g/min whereas oxygen inhalation produced no reliable change in CBF (-1.15 + or - 2.81 ml/100 g/min). In both patients and controls, carbogen was as efficient as oxygen in increasing Sa(O2) or PaO(2) values. The study demonstrates that concomitant increases of CBF and Sa(O2) are readily obtained with carbogen, while oxygen increases only Sa(O2). Thus, carbogen improves oxygen transport to brain tissue more efficiently than oxygen alone. Further studies with more subjects are, however, needed to investigate the applicability of carbogen for long-term inhalation and to assess its therapeutic benefits in acute stroke patients.

Safety and Efficacy of MRI-Based Selection for Recombinant Tissue Plasminogen Activator Treatment: Responder Analysis of Outcome in the 3-Hour Time Window

Introduction: The use of MRI may alter the target population for intravenous recombinant tissue plasminogen activator (rtPA) treatment relative to conventional CT. If selection changes, it remains crucial to demonstrate safety and efficacy of rtPA for the overall population, as well as in subpopulations hypothesized to benefit from MRI. Materials and Methods: Clinical outcome and incidence of symptomatic intracerebral hemorrhage (ICH) was recorded in 112 consecutive patients treated with intravenous rtPA (0–3 h) with MRI as first-choice imaging modality. According to the responder analysis, favorable outcome was separately defined for mild (NIHSS <8; n = 51), moderate (NIHSS 8–14; n = 30) and severe (NIHSS >14; n = 31) stroke. Results: Eighty-three patients were treated with rtPA after MRI, and 29 after CT. Adjusted for baseline severity, 42% of all patients had a favorable outcome, compared to 37% in NINDS. Among patients with severe stroke, MR-selected patients showed a good outcome in 52% of patients compared to 29% in NINDS (p < 0.05). Symptomatic ICH occurred in 2 patients (1.9 %), and 7 patients died during hospitalization (6.3%). Conclusion: MRI-based rtPA is safe and time-efficient. Outcome data compares well with NINDS data. Diagnostic information obtained from multimodal MRI may affect the target group. Our data support the hypothesized benefit of MRI in patients with severe stroke.

Feasibility and logistics of MRI before thrombolytic treatment

Objectives –  The study analyzes feasibility and time‐delays in Magnetic resonance imaging (MRI) based thrombolysis and estimate the impact of MRI on individual tissue plasminogen activator (rtPA) treatment.

Variable ATP Yields and Uncoupling of Oxygen Consumption in Human Brain

The distribution of brain oxidative metabolism values among healthy humans is astoundingly wide for a measure that reflects normal brain function and is known to change very little with most changes of brain function. It is possible that the part of the oxygen consumption rate that is coupled to ATP turnover is the same in all healthy human brains, with different degrees of uncoupling explaining the variability of total oxygen consumption among people. To test the hypothesis that about 75% of the average total oxygen consumption of human brains is common to all individuals, we determined the variability in a large group of normal healthy adults. To establish the degree of variability in different regions of the brain, we measured the regional cerebral metabolic rate for oxygen in 50 healthy volunteers aged 21-66 and projected the values to a common age of 25.Within each subject and region, we normalized the metabolic rate to the population average of that region. Coefficients of variation ranged from 10 to 15% in the different regions of the human brain and the normalized regional metabolic rates ranged from 70% to 140% of the population average for each region, equal to a two-fold variation. Thus the hypothetical threshold of oxygen metabolism coupled to ATP turnover in all subjects is no more than 70% of the average oxygen consumption of that population.

Neuroimaging of mirtazapine enantiomers in humans

IntroductionMirtazapine is a racemic antidepressant with a multireceptor profile. Previous studies have shown that the enantiomers of mirtazapine have different pharmacologic effects in the brain of laboratory animals.Materials and methodsIn the present study, we used positron emission tomography (PET) and autoradiography to study effects of (R)- and (S)-[11C]mirtazapine in the human brain. Detailed brain imaging by PET using three methods of kinetic data analysis showed no reliable differences between regional binding potentials of (R)- and (S)-[11C]mirtazapine in healthy subjects.ResultsAutoradiographic studies carried out in whole hemispheres of human brain tissue showed, however, that (R)- and (S)-mirtazapine differ markedly as inhibitors of [3H]clonidine binding at α2-adrenoceptors.ConclusionThe multireceptor binding profiles of mirtazapine enantiomers, along with individual differences between subjects, may preclude PET neuroimaging from demonstrating reliable differences between the regional distribution and binding of (R)- and (S)-[11C]mirtazapine in the living human brain.