Yasuhiro Hasegawa

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

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 ΔADC, 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 ΔADC values were not below −0.25 × 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. These results suggest that measurement of ΔADC can provide information that will enable the clinician to discriminate between irreversible and potentially reversible ischemic regions before reperfusion is performed.

Acetazolamide Reactivity on 123I-IMP Single Photon Emission Computed Tomography in Patients with Major Cerebral Artery Occlusive Disease: Correlation with Positron Emission Tomography Parameters

Single photon emission computed tomography (SPECT) with acetazolamide challenge has increasingly been used for evaluating hemodynamic reserve in stroke patients. The accuracy of this test, however, has not been validated with positron emission tomography (PET). In 14 patients who had occlusive disease of the internal carotid artery or the trunk of the middle cerebral artery (MCA) with minimal or no infarction on computed tomography (CT) and magnetic resonance imaging (MRI), we compared acetazolamide reactivity on SPECT with N-isopropyl-p-[123I]-iodoamphetamine to hemodynamic parameters determined with gas inhalation labeled 15O steady-state PET studies. The asymmetry index (AI)—i.e., the percentage of the activity rate of the ischemic MCA territory versus the contralateral one, was determined by SPECT. Acetazolamide reactivity expressed as ΔAI, or change in AI after acetazolamide challenge, was significantly lower in seven patients than −8.4%, the lower limit of the 95% confidence interval for the normal reactivity. Values of ipsilateral CBF, cerebral blood volume (CBV)/CBF, and oxygen extraction fraction (OEF) and contralateral OEF were significantly different between patients with normal and reduced acetazolamide reactivity. Values of AAI were correlated with OEF (r = −0.87; p < 0.001) and CBV/CBF (r = −0.56; p < 0.05). All patients with OEF >0.52, the mean + 2 SD calculated from five normal volunteers, also had reduced acetazolamide reactivity, while the patients with normal OEF values had normal reactivity. The present study has demonstrated that SPECT studies with an acetazolamide challenge can detect the Stage II hemodynamic failure.

Periostin as a Novel Factor Responsible for Ventricular Dilation

Background—Periostin is highly expressed in the myocardium in patients with heart failure. However, no report has documented the function of periostin. To identify the function of periostin in the pathophysiology of heart failure, overexpression or loss of function of the periostin gene was examined by direct transfection into the rat heart. Methods and Results—Rats transfected with the periostin gene by the HVJ-liposome method showed left ventricular (LV) dilation as assessed by echocardiography, accompanied by an increase in periostin expression. Consistently significant differences were observed in LV pressure, LV end-diastolic pressure, LV dP/dtmax, and LV dP/dtmin at 6 and 12 weeks after transfection in rats transfected with the periostin gene, accompanied by a decrease in cardiac myocytes and an increase in collagen deposition. Importantly, periostin has the ability to inhibit the spreading of myocytes and the adhesion of cardiac fibroblasts with or without fibronectin. Markers of cardiac dysfunction such as brain natriuretic peptide and endothelin-1 gene expression were significantly increased after transfection in the LV of rats transfected with the periostin gene. These data demonstrate that overexpression of the periostin gene led to cardiac dysfunction. Thus, we examined the inhibition of periostin in Dahl salt-sensitive rats by an antisense strategy because periostin is highly expressed in heart failure. Importantly, inhibition of periostin gene expression resulted in a significant increase in survival rate, accompanied by an improvement of LV function. Conclusion—The present study demonstrates the contribution of the periostin gene to cardiac dilation in animal models. Inhibition of periostin might become a new therapeutic target for the treatment of heart failure.

Severe Transient Hypoglycemia Causes Reversible Change in the Apparent Diffusion Coefficient of Water

BACKGROUND AND PURPOSE The aim of this study was to determine the effects of temporary severe hypoglycemia on the apparent diffusion coefficient (ADC) acquired by diffusion-weighted MRI of brain water with the use of serial multislice ADC mapping in rats. Severe hypoglycemia reduces the extracellular space volume, as does ischemia. Demonstrating a reduction of ADC with hypoglycemia should increase our understanding of the mechanisms underlying ADC changes in ischemia and other conditions. METHODS Fasted rats were given regular insulin (15 IU/kg IP). Rats were subjected to 15 minutes (n = 5) and 50 minutes (n = 5) of temporary severe hypoglycemia, causing a transiently isoelectric electroencephalogram (EEG). ADC mapping was performed every 30 seconds beginning at the onset of isoelectricity for 8.5 minutes. ADC maps were also obtained later during the isoelectric EEG period and 10, 20, 30, and 40 minutes after glucose infusion. Control images were obtained from a separate group of animals suffering cardiac arrest (n = 5). RESULTS Abnormal ADC values were not observed before the onset of cerebral isoelectricity, except for isolated areas in the cortex and periventricular regions. Cortical ADC values globally declined at the onset of EEG isoelectricity. The ADC decline spread to subcortical regions within a few minutes. During the isoelectric period, significant declines of ADC values (27% to 45%) occurred in the entire brain. Glucose infusion normalized most of the ADC changes, even after a 50-minute period of isoelectricity. CONCLUSIONS ADC mapping during hypoglycemia clearly demonstrates changes likely related to energy depletion. Most of these ADC declines were reversible. Hypoglycemia is a condition known to be associated with shrinkage of the extracellular space. These observations support the hypothesis that ADC reductions observed in ischemia are also related to shifts of water from the extracellular to the intracellular compartment.

Effect of Acetazolamide Reactivity and Long-term Outcome in Patients With Major Cerebral Artery Occlusive Diseases

Background and Purpose—It remains unclear whether hemodynamic insufficiency plays a major role in ischemic events. We performed a prospective follow-up study in ischemic stroke patients with occlusive large-artery diseases to determine whether stroke recurrence is related to reduced vasodilatory capacity, judged with single-photon emission CT and acetazolamide (ACZ) challenge. Methods—During the period from 1987 to 1995, we examined cerebral vasodilatory capacity with single-photon emission CT and an ACZ challenge in 105 consecutive stroke patients with severe stenosis (>75% in diameter) or occlusion of the internal carotid artery or the trunk of the middle cerebral artery who had no or minimal infarcts on CT. According to criteria reported earlier, the patients were divided into two groups: normal (negative ACZ, n=50) or reduced ACZ reactivity (positive ACZ, n=55). They were prospectively followed at regular intervals for a median period of 2.7 years. Results—The Kaplan-Meier analysis revealed no differe...

Multislice diffusion mapping for 3-D evolution of cerebral ischemia in a rat stroke model

Article abstract-Diffusion-weighted magnetic resonance imaging (DWI) can quantitatively demonstrate cerebral ischemia within minutes after the onset of ischemia. The use of a DWI echo-planar multislice technique in this study and the mapping of the apparent diffusion coefficient (ADC) of water, a reliable indicator of ischemic regions, allow for the detection of the three-dimensional (3-D) evolution of ischemia in a rat stroke model. We evaluated 13 time points from 5 to 180 minutes after occlusion of the middle cerebral artery (MCA) and monitored the 3-D spread of ischemia. Within 5 minutes after the onset of ischemia, regions with reduced ADC values occurred. The core of the lesion, with the lowest absolute ADC values, first appeared in the lateral caudoputamen and frontoparietal cortex, then spread to adjacent areas. The volume of ischemic tissue was 224 +\- 48.5 mm3 (mean +\- SEM) after 180 minutes, ranging from 92 to 320 mm3, and this correlated well with the corrected infarct volume at postmortem (194 +\- 23.1 mm3, r = 0.72, p < 0.05). This experiment demonstrated that 3-D multislice diffusion mapping can detect ischemic regions noninvasively 5 minutes after MCA occlusion and follow the development of ischemia. The distribution of changes in absolute ADC values within the ischemic region can be followed over time, giving important information about the evolution of focal ischemia. NEUROLOGY 1995;45: 172-177

Routine Use of Intravenous Low-Dose Recombinant Tissue Plasminogen Activator in Japanese Patients General Outcomes and Prognostic Factors From the SAMURAI Register

Background and Purpose— A retrospective, multicenter, observational study was conducted to document clinical outcomes and to identify outcome predictors in patients treated with low-dose intravenous recombinant tissue plasminogen activator (0.6 mg/kg alteplase), which was approved in Japan in 2005, within 3 hours of stroke onset. Methods— Consecutive patients with stroke treated with recombinant tissue plasminogen activator in 10 Japanese stroke centers were included. Results— A total of 600 patients (377 men, 72±12 years old) were studied. Median National Institutes of Health Stroke Scale scores decreased from 13 before recombinant tissue plasminogen activator to 8 at 24 hours later. Symptomatic intracerebral hemorrhage within 36 hours with a ≥1-point increase from the baseline National Institutes of Health Stroke Scale score developed in 23 patients (3.8%; 95% CI, 2.6% to 5.7%). At 3 months, 43 patients had died (7.2%; 5.4% to 9.5%), and 199 patients (33.2%; 29.5% to 37.0%) had a modified Rankin Scale score ≤1. Analysis of 399 patients with a premorbid modified Rankin Scale score ≤1 who met the criteria of the European license (≤80 years old, an initial National Institutes of Health Stroke Scale score ≤24, etc) showed that 40.6% (35.9% to 45.5%) had a 3-month modified Rankin Scale score ≤1. After multivariate adjustment, younger age, lower initial National Institutes of Health Stroke Scale score, absence of internal carotid artery occlusion, higher Alberta Stroke Program Early CT Score on CT, and absence of intravenous antihypertensives just before recombinant tissue plasminogen activator were independently related to a 3-month modified Rankin Scale score ≤1. Congestive heart failure and hyperglycemia were independently related to mortality. Conclusions— Three-month outcomes of patients receiving low-dose intravenous recombinant tissue plasminogen activator therapy in the present study were similar to those from postmarketing surveys using 0.9 mg/kg alteplase.

A radiological analysis of heart sympathetic functions with meta-[123I] iodobenzylguanidine in neurological patients with autonomic failure

Cardiac scintigraphy with meta-[123I]iodobenzylguanidine (MIBG) is used to assess cardiac sympathetic function. We performed [123I]MIBG scintigraphy in 7 patients with neurological diseases presenting orthostatic hypotension and other autonomic failures (AF), 22 neurological patients without AF, and 9 healthy subjects. Thallium scintigraphy and echocardiography were also performed in all subjects. In this series, patients with any evidence of cardiac dysfunction were excluded. No [123I]MIBG accumulation was observed in all patients with AF, and cardiac defects were noted in 7 patients (5 with Parkinsons disease [PD], 2 with spinocerebellar degenerations [SCD]), and in some patients without AF. In contrast, the distribution of [123I]MIBG was normal in all the healthy subjects. No decrease in [123I]MIBG accumulation was resulted from drug therapy (droxidopa, amezinium and thyrotropin-releasing hormone). In conclusion, reduced accumulation on [123I]MIBG scintigraphy may be due to myocardial beta-adrenoceptor dysfunction or reduced central sympathetic activity of the heart, or both.

Temperature dependent change of apparent diffusion coefficient of water in normal and ischemic brain of rats

To identify the temperature dependent change of the apparent diffusion coefficient (ADC) of water in brain tissue, the ADC values of normal rat brain were measured over a range of body temperatures with monitoring of head temperature using a small water reference implanted under the temporalis muscle. An initial experiment using thermocouples implanted into the cortex, caudate-putamen, temporalis muscle, and rectum demonstrated that temperature in all regions were highly correlated over a temperature range from 33 to 39°C. In another group of normal rats, brain ADC values varied almost uniformly with body temperature over the temperature range 33–39°C, implying that brain ADC values accurately reflect changes in brain temperature. The effects of focal ischemia and administration of the noncompetitive N-methyl-d-aspartate (NMDA) antagonist, CNS-1102, on ADC were also examined, using the suture middle cerebral artery (MCA) occlusion model while maintaining the body temperature at 37°C. ADC values and therefore brain temperature in the nonischemic and ischemic hemispheres were not affected by the drug. These experiments suggest that brain ADC measurement could be useful in animal studies and, potentially, in humans to assess the effects of pharmacologic intervention on brain temperature.

Sequential change of hemodynamic reserve in patients with major cerebral artery occlusion or severe stenosis

SummaryTo identify regional vasodilatory capacity and its sequential change, we evaluated prospectively a total of 78 acetazolamide tests in 51 patients with occlusion or greater than 75% stenosis of the carotid or middle cerebral arteries. The relative distribution of cerebral blood flow was determined by single photon emission computed tomography usingN-isopropyl-p-[123I]-iodoamphetamine before and after intravenous injection of acetazolamide. Reduced vasodilatory capacity was demonstrated in 20 patients (38%), including 5 patients with hemodynamic transient ischemic attacks or infarction. Follow-up acetazolamide tests revealed asymptomatic progression of the arterial lesion (from stenosis to occlusion) in 1 patient and almost complete improvement of vasodilatory capacity in 5 patients, including 3 without surgical intervention. During an average follow-up period of 18.5 months, 4 patients died from cardiac causes or neoplasm; no neurovascular events occurred. Much larger numbers of patients with longer observation periods will be necessary to clarify the contribution of chronic hemodynamic failure to subsequent stroke. However, the present data indicate that the acetazolamide test is useful for assesssing the course of high grade stenosis or occlusion of major cerebral arteries.