Kazunori Terasaki

Effects of EC-IC bypass surgery on cognitive impairment in patients with hemodynamic cerebral ischemia

BACKGROUND Chronic ischemia because of internal carotid artery (ICA) occlusive disease may result in dementia. The goal of this study was to assess cognitive impairment in symptomatic patients with hemodynamic cerebral ischemia and determine the efficacy of extracranial-intracranial (EC-IC) bypass in restoring neuropsychologic integrity. METHODS Twenty-five patients were defined by clinical and neuroradiological criteria as suffering from hemodynamic cerebral ischemia because of unilateral ICA or middle cerebral artery occlusion. Subjects underwent assessment of cerebral blood flow and metabolism using positron emission tomography (PET) before and after bypass surgery. To provide data regarding cognition, changes in the Japanese Wechsler Adult Intelligence Scale Revised (WAIS-R) were recorded. RESULTS Preoperative study of patients revealed significant impairment in cerebral blood flow and metabolism as well as reduced WAIS-R score. Among the factors considered, only elevated regional oxygen extraction fraction and reduced regional cerebral metabolic rates of oxygen were significantly associated with preoperative cognitive impairment (p = 0.0032 and p = 0.0255, respectively; logistic regression analysis). After bypass surgery, cerebral blood flow and metabolism improved significantly, and the WAIS-R score increased. CONCLUSIONS Symptomatic patients with hemodynamic cerebral ischemia displayed impaired cognition that was partially alleviated with EC-IC bypass surgery.

Cerebral Hyperperfusion after Carotid Endarterectomy is Associated with Preoperative Hemodynamic Impairment and Intraoperative Cerebral Ischemia

The aim of this study was to investigate whether postoperative hyperperfusion is associated with preoperative cerebral hemodynamic impairment due to chronic ischemia and with acute cerebral ischemia during clamping of the internal carotid artery (ICA) during carotid endarterectomy (CEA). Transcranial cerebral oxygen saturation (SO2) was monitored intraoperatively using near-infrared spectroscopy in 89 patients undergoing CEA for ipsilateral ICA stenosis (> 70%). Cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) to acetazolamide were also measured using single photon emission computed tomography (SPECT) before CEA. In addition, CBF was measured immediately after CEA and on the third postoperative day. Hyperperfusion (CBF increase > 100% compared with preoperative values) was observed immediately after CEA in 10 of 18 patients (56%) with reduced preoperative CVR. Also, post-CEA hyperperfusion was observed in nine of 16 patients (56%) whose SO2 during clamping of the ICA decreased to less than 90% of the preclamping value. Logistic regression analysis showed that reduced preoperative CVR and reduced SO2 during ICA clamping were significant independent predictors of the development of hyperperfusion immediately after CEA. In fact, all patients with reduced preoperative CVR and reduced SO2 during ICA clamping developed post-CEA hyperperfusion, and two of these patients developed cerebral hyperperfusion syndrome. These data suggest that development of cerebral hyperperfusion after CEA is associated with preoperative hemodynamic impairment and intraoperative cerebral ischemia.

Use of cerebrovascular reactivity in patients with symptomatic major cerebral artery occlusion to predict 5-year outcome: comparison of xenon-133 and iodine-123-IMP single-photon emission computed tomography.

The aim of this prospective study was to investigate whether decreased cerebrovascular reactivity to acetazolamide, as determined by single-photon emission computed tomography (SPECT), is an independent predictor of the 5-year risk of subsequent stroke in patients with symptomatic major cerebral artery occlusion. Cerebrovascular reactivity to acetazolamide in the middle cerebral artery (MCA) territory ipsilateral to the occluded artery was determined on the basis of two different methodologies: cerebral blood flow (CBF) percent change obtained quantitatively from xenon-133 (133Xe) SPECT, and asymmetry index (AI) percent change obtained qualitatively from N-isopropyl-p-[123I]-iodoamphetamine (IMP) SPECT. Seventy patients with unilateral internal carotid artery or MCA occlusion were divided into two groups within each SPECT methodology (normal or decreased CBF percent change and AI percent change) and followed up for 5 years. Cumulative recurrence-free survival rates for patients with decreased CBF percent change were significantly lower than for those with normal CBF percent change (P = 0.0205). There was no significant difference in cumulative recurrence-free survival rates between patients with decreased AI percent change and those with normal AI percent change. Only decreased CBF percent change was a significant independent predictor of stroke recurrence (P = 0.0051). The present study demonstrated that decreased cerebrovascular reactivity to acetazolamide determined quantitatively by Xe SPECT is an independent predictor of the 5-year risk of subsequent stroke in patients with symptomatic major cerebral artery occlusion, and that the qualitative method using I-IMP SPECT is a poor predictor of the risk of subsequent stroke in this type of patient.

[18F]Fluoromethyl triflate, a novel and reactive [18F]fluoromethylating agent: Preparation and application to the on-column preparation of [18F]fluorocholine

The production and use of [18F]fluoromethyl triflate ([18F]CH2FOTf), a more reactive [18F]fluoromethylating agent than [18F]fluoromethyl bromide ([18F]CH2BrF), is described. [18F]CH2FOTf was prepared from [18F]CH2BrF. The latter was synthesized by nucleophilic substitution of CH2Br2 with no-carrier-added [18F]fluoride and purified by four Sep-Pak Plus silica cartridges connected in series. It was then quantitatively converted on-line to [18F]CH2FOTf by passing through a heated AgOTf column. Decay-corrected radiochemical yields of [18F]CH2FOTf based on [18F]fluoride were 47 +/- 8% (n = 20). Both [18F]CH2BrF and [18F]CH2FOTf were applied to solid-supported [18F]fluoromethylation of N,N-dimethylaminoethanol on a Sep-Pak Plus C18 cartridge to produce the 18F-labeled choline analogue, (beta-hydroxyethyl)dimethyl-[18F]fluoromethylammonium ([18F]fluorocholine). Depending on flow rate and amount of precursor used, decay corrected radiochemical yields of [18F]fluorocholine from [18F]CH2BrF ranged from 6% to 63%, while [18F]CH2FOTf afforded yields of more than 80%. Thus, by using the latter reagent and a subsequent purification on a Sep-Pak Accell CM cartridge, [18F]fluorocholine was produced from [18F]fluoride in overall radiochemical yields of 40% (decay corrected) in less than 30 min.

Postcarotid endarterectomy improvement in cognition is associated with resolution of crossed cerebellar hypoperfusion and increase in 123I-iomazenil uptake in the cerebral cortex: a SPECT study.

Background: The purpose of the present study was to investigate whether resolution of crossed cerebellar hypoperfusion (CCH) and increase in 123I-iomazenil (IMZ) uptake in the ipsilateral cerebral cortex after carotid endarterectomy (CEA) are associated with postoperative improvement of cognitive function. Methods: Neuropsychological testing was performed preoperatively and after 1 postoperative month in 79 patients undergoing CEA for ipsilateral internal carotid artery stenosis (≧70%). Brain perfusion single photon emission computed tomography (SPECT) using N-isopropyl-p-123I-iodoamphetamine and 123I-IMZ SPECT were also performed before and after surgery. Data were analyzed using a three-dimensional stereotaxic region of interest template. Results: Seven patients (9%) showed improvement in postoperative cognitive function. All the 7 patients exhibited both postoperative increase in blood flow in the ipsilateral cerebral cortex and resolution of CCH. Five patients (6%) had a postoperative hemispheric increase in 123I-IMZ uptake, and cognitive function improved in all of these 5 patients. Analysis by a receiver operating characteristic (ROC) curve was used to estimate the ability to discriminate between patients with and without postoperative cognitive improvement. The area under the ROC curve was significantly greater when analyzing the magnitude of postoperative resolution of CCH (0.991; 95% CI 0.984–1.001) or postoperative hemispheric increase in 123I-IMZ uptake (0.981; 95% CI 0.972–0.999) when compared with the magnitude of postoperative increase in cerebral blood flow (0.929; 95% CI 0.886–0.971) (p < 0.05). Conclusions: Resolution of CCH and increase in 123I-IMZ uptake in the ipsilateral cerebral cortex after CEA is associated with postoperative improvement in cognitive function. These results may indicate that cognitive impairment is related to a state of potentially reversible central benzodiazepine receptor downregulation in the cortex in response to transient ischemic attack or minor stroke.

Brain Temperature Measured Using Proton MR Spectroscopy Detects Cerebral Hemodynamic Impairment in Patients With Unilateral Chronic Major Cerebral Artery Steno-Occlusive Disease Comparison With Positron Emission Tomography

Background and Purpose— Brain temperature is determined by the balance between heat produced by cerebral energy turnover and heat removed by cerebral blood flow. The purpose of the present study was to investigate whether brain temperature measured noninvasively using proton MR spectroscopy can detect cerebral hemodynamic impairment in patients with unilateral chronic internal carotid or middle cerebral artery occlusive disease when compared with positron emission tomography. Methods— Brain temperature, cerebral blood flow, and metabolism were measured using proton MR spectroscopy and 15O-positron emission tomography, respectively, in 21 normal subjects and 37 patients. Positron emission tomography images were coregistered with MR images and resliced automatically using image analysis software. Regions of interest placed in both cerebral hemispheres on MR images were automatically superimposed in these resliced positron emission tomography images. Results— A significant correlation was observed between brain temperature difference (affected hemisphere–contralateral hemisphere) and both cerebral blood volume and oxygen extraction fraction ratio (affected hemisphere/contralateral hemisphere; r=0.607; P=0.0004 and r=0.631; P=0.0002). With abnormally elevated cerebral blood volume or oxygen extraction fraction ratio defined as higher than the mean +2 SDs obtained from normal subjects, brain temperature difference provided 86% or 92% sensitivity and 87% or 84% specificity with 80% or 73% positive and 91% or 95% negative predictive values for detecting abnormally elevated cerebral blood volume or oxygen extraction fraction ratios, respectively. Conclusions— Brain temperature measured using proton MR spectroscopy can detect cerebral hemodynamic impairment in patients with unilateral chronic major cerebral artery steno-occlusive disease.

Central benzodiazepine receptor binding potential and CBF images on SPECT correlate with oxygen extraction fraction images on PET in the cerebral cortex with unilateral major cerebral artery occlusive disease.

Oxygen extraction fraction (OEF) is a key predictor of stroke recurrence in patients with symptomatic major cerebral arterial occlusive disease. The purpose of the present study was to compare central benzodiazepine receptor binding potential (BRBP) and cerebral blood flow (CBF) images on SPECT with OEF images on PET in patients with chronic unilateral middle cerebral artery (MCA) or internal carotid artery (ICA) occlusive disease. Methods: OEF, CBF, and BRBP were assessed using 15O PET and N-isopropyl-p-123I-iodoamphetamine and 123I-iomazenil SPECT, respectively, in 20 healthy subjects and in 34 patients with unilateral MCA or ICA occlusive disease. All images were transformed into the standard brain size and shape by linear and nonlinear transformation using statistical parametric mapping for anatomic standardization. A region of interest (ROI) was automatically placed according to the arterial supply using a 3-dimensional stereotactic ROI template, and the ratio of the value in the affected side to that in the contralateral side was calculated in each image. Results: Among patients with occlusive disease, a significant positive correlation was observed between PET OEF and SPECT BRBP/CBF ratios in 3 cerebral cortical regions (r = 0.851, P < 0.0001, for anterior cerebral artery [ACA] ROI; r = 0.807, P < 0.0001, for MCA ROI; and r = 0.774, P < 0.0001, for posterior cerebral artery [PCA] ROI), but there were no correlations between these 2 parameters in the basal ganglia or the cerebellum. When an abnormally elevated PET OEF ratio was defined as a value greater than the mean + 2 SDs obtained in healthy subjects, sensitivity and specificity were, respectively, 100% and 96% for the ACA ROI, 100% and 89% for the MCA ROI, and 100% and 93% for the PCA ROI for the SPECT BRBP/CBF ratio for detecting an abnormally elevated PET OEF ratio. Conclusion: BRBP/CBF images on SPECT correlate with OEF images on PET in a specific clinical setting—that is, in the cerebral cortex of patients with chronic unilateral MCA or ICA occlusive disease.

Augmentation effects of lymphocyte activation by antigen-presenting macrophages on FDG uptake

Objective: Research on FDG-uptake by blood cells has revealed that FDG is incorporated by macrophages and granulocytes, as well as activated lymphocytes. These characteristics of FDG suggest the possibility of visualizing the distribution of immunocytes in target organs. The aim of this study was to investigate if mouse spleen-derived lymphocytes, activated by macrophages presenting sheep red blood cell (sRBC) antigens, could be traced by FDG.Methods: One percent of a sRBC suspension was injected into the peritoneal cavity of mice thereby creating immunity to the sRBC antigen. The splenocytes, consisting mostly of lymphocytes, were isolated, and serum containing the anti-sRBC antibody was mixed with sRBC to prepare sRBC-antibody complexes (sRBC-AbCs). Then five percent of a thioglycolate medium was injected into the peritoneal cavity of the same mice, and macrophages of ascitic cell origin were obtained. These macrophages were added to the sRBC-AbCs to induce sRBC antigen presenting macrophages. These were incubated with splenocytes obtained from sRBC immunized mouse (sRBC immunized splenocytes) or nonimmunized splenocytes to induce a T cell immune response. [3H]deoxyglucose ([3H]DG) and FDG were incorporated in splenocytes, and the quantity of their uptake was measured.Results: [3H]DG uptake by sRBC-immunized splenocytes was about eleven times as high as that of non-immunized splenocytes. In contrast, [3H]DG uptake by sRBC-immunized splenocytes, co-cultured with macrophages phagocytizing sRBC-AbCs, was about 40 times higher compared with non-immunized splenocytes. Splenocytes in non-immunized mice picked up very little [3H]DG, despite co-culture with macrophages phagocytizing sRBC-AbCs. Similar tendencies were observed with FDG.Conclusions: These results suggest that the SUV calculated in PET reflects not only the number of lymphocytes, but also the activation state of the lymphocytes themselves. In addition, the biodistribution of antigen specific lymphocytes, that have been taken up FDGin vitro and returned to the body, can be observed through PET.

Accuracy of central benzodiazepine receptor binding potential/cerebral blood flow SPECT imaging for detecting misery perfusion in patients with unilateral major cerebral artery occlusive diseases: comparison with cerebrovascular reactivity to acetazolamide and cerebral blood flow SPECT imaging.

Purpose: The aim of the present study was to determine whether central benzodiazepine receptor binding potential (BRBP)/cerebral blood flow (CBF) or a combination of CBF and cerebrovascular reactivity (CVR) to acetazolamide on single-photon emission computed tomography (SPECT) more accurately detects misery perfusion, indicating elevation of absolute value of oxygen extraction fraction (OEF) on positron emission tomography (PET), in patients with unilateral major cerebral artery occlusive diseases. Methods: In 84 patients, OEF, CBF, CVR to acetazolamide, and BRBP were assessed using 15O-PET and N-isopropyl-p-[123I]-iodoamphetamine and [123I]-iomazenil SPECT, respectively. A region of interest was automatically placed in the middle cerebral artery territory using a 3-dimensional stereotactic region of interest template. Results: Sensitivity, specificity, and positive and negative predictive values for the affected side-to-contralateral side asymmetry on SPECT-BRBP/CBF to detect the abnormally elevated PET-OEF in the affected hemisphere were 100%, 86.4%, 66.7%, and 100%, respectively. Area under the receiver operating characteristic curve in detecting the abnormally elevated PET-OEF in the affected hemisphere did not differ between analysis of the combination of SPECT-CBF and SPECT-CVR in the affected hemisphere (0.89; 95% confidence interval, 0.80–0.94) and that of the affected side-to-contralateral side asymmetry on SPECT-BRBP/CBF (0.93; 95% confidence interval, 0.86–0.97). The combination of the 3 detected abnormally elevated PET-OEF with 97.0% specificity and 90.0% positive predictive value. Conclusions: The accuracy of central BRBP/CBF asymmetry on SPECT is equivalent to that of the combination of CBF and CVR to acetazolamide on SPECT for detecting misery perfusion in patients with unilateral major cerebral artery occlusive disease.

Effect of combination therapy with the angiotensin receptor blocker losartan plus hydrochlorothiazide on brain perfusion in patients with both hypertension and cerebral hemodynamic impairment due to symptomatic chronic major cerebral artery steno-occlusive disease: a SPECT study.

Background: While the combination of an angiotensin receptor blocker with thiazide diuretics produces a clinically beneficial reduction in blood pressure in patients who otherwise only partially respond to monotherapy with an angiotensin receptor blocker, blood pressure-lowering therapy with combination antihypertensive drug regimens in patients with cerebral hemodynamic impairment may adversely affect cerebral hemodynamics. The purpose of the present exploratory study was to determine whether blood pressure-lowering therapy with the combination of the angiotensin receptor blocker losartan plus hydrochlorothiazide (LPH) worsens brain perfusion in patients with both hypertension and cerebral hemodynamic impairment due to symptomatic chronic major cerebral artery steno-occlusive disease. Methods: Patients with losartan-resistant hypertension and reduced cerebrovascular reactivity (CVR) to acetazolamide due to symptomatic chronic internal carotid artery (ICA) or middle cerebral artery (MCA) steno-occlusive disease were prospectively entered into the present study and received 50 mg/day of losartan plus 12.5 mg/day of hydrochlorothiazideat 14 weeks after the last ischemic event. Cerebral blood flow (CBF) and CVR were measured before and 12 weeks after initiating LPH using N-isopropyl-p-[123I]-iodoamphetamine single-photon emission computed tomography (SPECT). A region of interest (ROI) was automatically placed in the MCA territory on each SPECT image using a three-dimensional stereotactic ROI template. Results: None of the 18 patients who participated in the study experienced any new neurological symptoms or adverse effects related to antihypertensive drugs. Systolic (p < 0.001) and diastolic (p < 0.001) blood pressures were significantly reduced after the administration of LPH, with average reductions of 11 mm Hg in systolic blood pressure and 10 mm Hg in diastolic blood pressure. While in the affected hemisphere CBF did not differ between measurements taken before and after the administration of LPH, CVR was significantly higher after the administration of LPH than before (p = 0.007) and was significantly improved in 5 of 18 patients. In the contralateral hemisphere, CBF and CVR did not differ between measurements taken before and after the administration of LPH. There were no patients who experienced a significant deterioration in CBF or CVR in the affected or contralateral hemisphere after the administration of LPH. Conclusions: Although the present study was exploratory and its results were preliminary due to the small sample size, the current data suggest that blood pressure-lowering therapy with LPH apparently does not result in worsening of cerebral hemodynamics in patients with both hypertension and cerebral hemodynamic impairment due to symptomatic chronic ICA or MCA steno-occlusive disease.