Studies in the 1990s demonstrated that misery perfusion is a predictor of subsequent stroke in medically treated patients with symptomatic major cerebral artery disease. A recent randomized ...controlled trial demonstrated no benefit of bypass surgery for such patients. In this light, outcome in patients with misery perfusion has regained interest. The purpose of this study was to determine whether misery perfusion is still a predictor of subsequent stroke despite recent improvements in medical treatment for secondary prevention of stroke, and if so, whether the predictive value of misery perfusion has changed in recent years. We prospectively studied 165 non-disabled patients with symptomatic atherosclerotic internal carotid artery or middle cerebral artery occlusive diseases who underwent positron emission tomography from 1999 to 2008. Misery perfusion was defined as decreased cerebral blood flow, increased oxygen extraction fraction and decreased ratio of cerebral blood flow to blood volume in the hemisphere supplied by the diseased artery. All patients were followed up for 2 years until stroke recurrence or death. Bypass surgery was performed in 19 of 35 patients with and 16 of 130 patients without misery perfusion. The 2-year incidence of ipsilateral ischaemic stroke was six and four patients with and without misery perfusion, including two and one after surgery, respectively (P < 0.002). Total strokes occurred in nine patients with misery perfusion and 12 patients without (P < 0.01). The relative risk conferred by misery perfusion in whole sample was 6.3 (95% confidence interval 1.7-22.4, P < 0.005) for ipsilateral ischaemic stroke and 3.5 (95% confidence interval 1.4-8.9, P < 0.01) for all strokes, while the respective values in medically treated patients were 12.6 (95% confidence interval 2.7-57.8, P < 0.005) and 4.7 (95% confidence interval 1.3-16.3, P < 0.02). The all-stroke incidence in patients entering the study from 2004 to 2008 (4/72) was significantly lower than in those entering from 1999 to 2003 (17/93; P < 0.02), although the prevalence of misery perfusion or bypass surgery did not differ. Between these periods, patients without misery perfusion demonstrated a decrease in stroke rate (from 16.2% to 0%), but patients with misery perfusion did not (26.3 and 25.0%). In symptomatic major cerebral artery disease, misery perfusion remains a predictor of subsequent stroke, although the recurrence rate was lower than the previous study. In patients without misery perfusion, the risk of stroke was reduced over time. Thus, identification and stricter management of patients with misery perfusion are essential to further improve prognosis.
Rheumatoid arthritis (RA) has been attributed to the abnormal production of cytokine interleukin-6 (IL-6), which has a variety of physiological activities. In vivo IL-6-receptor imaging provides ...useful suggestions regarding the mechanism of anti-IL-6-receptor antibody action and indicates a basic therapeutic strategy for treating RA. Therefore, this study was designed to establish a method for radiolabeling anti-IL-6-receptor antibodies and to investigate the feasibility of using radiolabeled anti-IL-6-receptor antibodies in the scintigraphic imaging of lesions in an animal RA model. Anti-IL-6-receptor antibodies were conjugated with a bifunctional chelating agent, hydrazinonicotinamide (HYNIC), and radiolabeled with technetium-99m (99mTc) using the ligand exchange reaction of 99mTc-tricine complex. The binding affinity was estimated using the U266 cell line. Whole body scintigraphy, biodistribution and autoradiography were undertaken in mice containing synovial cells that had been transplanted from an RA patient. Our findings showed that the antibodies accumulated in the implanted tissue. When radiolabeled anti-IL-6-receptor antibodies are used in scintigraphic imaging, the distribution of the IL-6-receptors is associated with the inflammatory cell infiltration that is seen in the early stage of RA. Accordingly, imaging with humanized anti-IL-6-receptor antibodies appears to be useful for detecting early pathophysiological conditions and assessing the efficacy of antibody treatment as well as the prognosis of patients with RA.
A decrease in the cerebral blood flow (CBF) response to acetazolamide may indicate an increase in cerebral blood volume (CBV) caused by reduced perfusion pressure in patients with major cerebral ...artery steno-occlusive lesions. However, a decrease in cerebral metabolic rate of oxygen (CMRO(2)) caused by ischemic changes may also decrease the CBF response to acetazolamide by decreasing the production of carbon dioxide. The purpose of this study was to determine whether the values of CBV and CMRO(2) are independent predictors of the CBF response to acetazolamide in major cerebral arterial occlusive disease. We used positron emission tomography to study 30 patients with major cerebral artery steno-occlusive lesions. The CBF response to acetazolamide was assessed by measuring baseline CBF and CBF 10 min after an intravenous injection of 1 g of acetazolamide. Multivariate analysis was used to test the independent predictive value of the CBV and CMRO(2) at baseline with respect to the percent change in CBF during acetazolamide administration. Both increased CBV and decreased CMRO(2) were significant and independent predictors of the reduced CBF response to acetazolamide. CBV accounted for 25% of the variance in the absolute change in CBF during acetazolamide administration and 42% of the variance in the percent change in CBF, whereas CMRO(2) accounted for 19% and 4% of the variance, respectively. In patients with major cerebral arterial occlusive disease, a decrease in CMRO(2) may contribute to the reduced CBF response to acetazolamide, although an increase in CBV appears to be the major contributing factor.
To evaluate a new simplified bolus method for measurement of cerebral perfusion and metabolism, the parametric images with that method were compared with those obtained from the conventional ...steady-state method with 15O-gas. The new method also provided images of arterial blood volume (V0), which is a different parameter from cerebral blood volume (CBV) obtained using a C15O technique. Seven healthy volunteers and 10 patients with occlusive cerebrovascular diseases underwent positron emission tomography (PET) scans with both methods. Three-weighted integration was applied to calculate regional cerebral blood flow (rCBF) and regional cerebral metabolic rate of oxygen (rCMRO2) in the bolus method. Global and regional CBF and CMRO2 in volunteers were compared between the two methods and used as control data. Regional values in patients also were evaluated to observe differences between the bilateral hemispheres. Both rCBF and rCMRO2 were linearly well correlated between the two methods, although global difference in CMRO2 was significant. The difference in each parametric image except for V0 was significant between the bilateral hemispheres in patients. The bolus method can simplify oxygen metabolism studies and yield parametric images comparable with those with the steady-state method, and can allow for evaluation of V0 simultaneously. Increase in CBV without a change in V0 suggested the increase might mainly be caused by venous dilatation in the ischemic regions.
To evaluate changes in cerebral hemodynamics and metabolism induced by acetazolamide in healthy subjects, positron emission tomography studies for measurement of cerebral perfusion and oxygen ...consumption were performed. Sixteen healthy volunteers underwent positron emission tomography studies with15O-gas and water before and after intravenous administration of acetazolamide. Dynamic positron emission tomography data were acquired after bolus injection of H215O and bolus inhalation of15O2. Cerebral blood flow, metabolic rate of oxygen, and arterial-to-capillary blood volume images were calculated using the three-weighted integral method. The images of cerebral blood volume were calculated using the bolus inhalation technique of C15O. The scans for cerebral blood flow and volume and metabolic rate of oxygen after acetazolamide challenge were performed at 10, 20, and 30 minutes after drug injection. The parametric images obtained under the two conditions at baseline and after acetazolamide administration were compared. The global and regional values for cerebral blood flow and volume and arterial-to-capillary blood volume increased significantly after acetazolamide administration compared with the baseline condition, whereas no difference in metabolic rate of oxygen was observed. Acetazolamide-induced increases in both blood flow and volume in the normal brain occurred as a vasodilatory reaction of functioning vessels. The increase in arterial-to-capillary blood volume made the major contribution to the cerebral blood volume increase, indicating that the raise in cerebral blood flow during the acetazolamide challenge is closely related to arterial-to-capillary vasomotor responsiveness.
To investigate changes in cerebral blood flow (CBF) and blood volume induced by acetazolamide (ACZ) in patients with a variable autoregulatory status responding to reduced perfusion pressure, PET ...measurements of hemodynamic parameters were performed on patients with cerebrovascular disease, and the relationships between the parameters were evaluated.
Sixteen patients with unilateral major cerebral arterial occlusive disease underwent PET studies with (15)O-gas and the steady-state method to obtain hemodynamic parameters in the brain. All patients and 8 healthy volunteers underwent H(2)(15)O PET at baseline and 10 min after ACZ injection to calculate the CBF and arterial-to-capillary blood volume (V(0)) based on a 2-compartment model.
The regional CBF (rCBF) and V(0) increased significantly after ACZ administration in volunteers and in the hemisphere contralateral to the ischemic side in patients. However, in a subgroup of patients with disease who showed a significant reduction in the rCBF increase in the ipsilateral hemisphere, the ACZ challenge caused a decrease in the rCBF even though the V(0) showed a significant increase. The reduction in the rCBF increase was associated with an asymmetric increase in oxygen extraction fraction (OEF) but not with an absolute OEF increase.
The increases in rCBF and V(0) induced by ACZ administration, as well as absolute OEF value in the baseline condition, did not necessarily parallel each other in the ipsilateral hemispheres of patients. Thus, the increase in rCBF after ACZ challenge may not represent vasodilatory capacity in patients with cerebrovascular disease, especially in the regions with a reduced rCBF response.
The changes in cerebral blood flow (CBF) and arterial-to-capillary blood volume (V(0)) induced by acetazolamide (ACZ) are expected to be parallel each other in the normal circulation; however, it has ...not been proven that the same changes in those parameters are observed in patients with cerebrovascular disease. To investigate the relationship between changes in CBF, vasodilatory capacity, and other hemodynamic parameters, the ACZ test was performed after an (15)O-gas PET study.
Twenty-two patients with unilateral major cerebral arterial occlusive disease underwent PET scans using the H(2)(15)O bolus method with the ACZ test after the (15)O-gas steady-state method. CBF and V(0) for each subject were calculated using the 3-weighted integral method as well as the nonlinear least-squares fitting method. After evaluation of accuracy in V(0) values, a new parameter, the CBF/V(0) ratio, which is expected to disclose arterial perfusion pressure, was also compared between the conditions.
The regional CBF (rCBF) and V(0) increased significantly after ACZ administration in the hemisphere contralateral to the ischemic side. However, in a subgroup of patients who showed a significant reduction in the rCBF increase in the ipsilateral hemisphere (group A), the ACZ injection caused no change or a slight decrease in rCBF even though the V(0) showed a significant increase. Thus, the increases in rCBF and V(0) did not necessarily parallel each other in the ipsilateral hemispheres of patients who have impaired cerebral circulation. A parameter defined by the rCBF/V(0) ratio decreased significantly in the ipsilateral hemisphere of group A after ACZ administration, although the ratio showed no change in the contralateral hemisphere or in the other subgroup (group B).
The change in the rCBF/V(0) ratio after ACZ challenge may represent an alteration in arterial perfusion pressure that is expected to indicate a critical hemodynamic status in patients with cerebrovascular disease, especially in patients who have a reduced rCBF response.
Acetazolamide, a carbonic anhydrase inhibitor, has an anticonvulsant effect which may result from a decrease in the efficacy of synaptic transmission due to a decrease of pH. Our previous study ...showed that acetazolamide induced a significant increase in global and regional cerebral blood flow (CBF), but caused no significant change in the cerebral metabolic rate of oxygen (CMRO
2). To investigate the effect of acetazolamide on the responses of CBF and CMRO
2 during neural stimulation, we used positron emission tomography to measure CBF and CMRO
2 in six normal volunteers at the fixation-only baseline visual state and during visual stimulation before and after administration of 1 g of acetazolamide. Visual stimulation induced a significant increase in CBF (33%) in the visual cortex compared with baseline values, but caused no significant change in CMRO
2, while no significant change in global CBF or CMRO
2 was found. During visual stimulation after acetazolamide administration, both global and visual cortical CBF and CMRO
2 showed similar changes compared with the respective baseline values (37 and 65% increases in CBF and 8 and 16% decreases in CMRO
2, respectively). When corrected by the global values, the magnitudes of the CBF and CMRO
2 responses to visual stimulation after acetazolamide administration were less than those before (20% vs 38% in CBF and −9% vs 3% in CMRO
2). Considering our previous observation that the effect of acetazolamide was similar throughout cerebral cortical regions, we suggest that acetazolamide decreases the responses of both CBF and CMRO
2 during visual stimulation, which indicates that this drug may affect neuronal excitability.
Decreased cerebral blood flow (CBF) response after acetazolamide administration may indicate increased cerebral blood volume (CBV) owing to reduced perfusion pressure from major cerebral artery ...steno-occlusive disease. However, decreased cerebral metabolic rate of oxygen (CMRO(2)) caused by neuronal damage or deafferentation may also decrease the CBF response to acetazolamide, which adds complexity to the assessment of autoregulatory vasodilatation. The purpose of this study was to investigate the relationship between CBF response to acetazolamide and CBV or CMRO(2) in a pure form of deafferentation, crossed cerebellar diaschisis (CCD).
We used positron emission tomography to study 17 patients with unilateral supratentorial infarct and contralateral cerebellar hypoperfusion. The CBF response to acetazolamide was assessed by measuring baseline CBF and CBF 10 minutes after an intravenous injection of acetazolamide. Multivariate analysis was used to test the independent predictive value of the CBV and CMRO(2) at baseline with respect to the change of CBF during acetazolamide administration.
Multivariate analysis revealed that in CCD CBV was significantly and independently associated with the percent change of CBF during acetazolamide administration (P <.0001), whereas CMRO(2) was not.
In deafferentation, changes in CBV may account for variations in CBF response to acetazolamide and decreased CMRO(2) may not affect CBF response to acetazolamide expressed as the percent change.
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