Characterization of 99mTc-bicisate as an agent for the measurement of cerebral blood flow with SPECT.
Explore the source record for details and available documents.
Alzheimer Disease↗
Biomedical subjects
N A Lassen
Publications and source records attributed to N A Lassen.
Use of 99mTc-bicisate in activation studies by split-dose technique.
The properties of the brain single photon emission computed tomography (SPECT) tracer 99mTc-bicisate (ethyl cysteinate dimer) were examined in regard to its use in test-retest studies with short-interval, split-dose studies. The stimulus applied in these tests was a visual activation by a "flickering chessboard" pattern. We used a fast dynamic SPECT (Tomomatic 232) recording eight slices. Twelve volunteers were assigned to two groups for reproducibility control and stimulation experiments, respectively. All were examined on 2 days. On the first day, only one injection was given in the resting state (t = 0), while two recordings were performed (t = 30 and t = 100), simulating the course and timing of a full split-dose study. The average washout of 8.3 +/- 1.0% was used as a correction on the second-day study. On that day the first injection was given during rest exactly as on day 1, allowing an estimate of day-to-day reproducibility. The second injection was made either in a resting state identical to the first or during visual stimulation. All images were normalized to mean brain count value. Results were analyzed in predefined anatomical regions of interest (ROIs). The day-to-day reproducibility was fair, with only one ROI (inferior frontal cortex) showing a significant 2% decrease. The studies of day 1 revealed a regional difference in observed washout ranging in the applied cortical ROIs from 7.9 to 11.5%.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Retention of 99mTc-bicisate in the human brain after intracarotid injection.
99mTc-bicisate (ECD) was injected as a bolus into the internal carotid artery, and cerebral uptake and retention were recorded with fast-rotating single photon emission computed tomography (SPECT) equipment in four patients suffering from temporal lobe epilepsy. Quantitative regional cerebral blood flow (rCBF) was measured tomographically with the 133Xe inhalation technique. We applied a three-compartment kinetic model and algorithms modified from a previous analysis of 99mTc d,l-hexamethylpropyleneamine oxide (HM-PAO) kinetics. The bicisate brain uptake and retention curve was very similar to that of HM-PAO, and it can be described by a triexponential function including an initial steep component representing the vascular transmitted spike, a second less steep component representing back-diffusion from brain tissue to blood, and a third, very slow component, representing the very slow loss due to incomplete retention of the deesterified hydrophilic metabolites. Computerized curve-fitting on data from three patients gave average kinetic values for the first-passage (unilateral) extraction of E = 0.60 (range, 0.59-0.61); the overall retained fraction of the tracer supplied was R = 0.44 (0.43-0.45), and the conversion/clearance ratio was alpha = k3/k2 = 2.59 (2.38-2.77). This alpha is higher than that for HM-PAO, and therefore bicisate uptake as a function of blood flow is more linear than in HM-PAO. Less correction for backdiffusion is therefore needed. From 1 to 24 h there was an average loss of hydrophilic tracer of 3.5%/h, but the late distribution images were essentially unchanged over time, pointing to practically the same rate of loss in all regions.
Adolescent↗
99mTc-bicisate reliably images CBF in chronic brain diseases but fails to show reflow hyperemia in subacute stroke: report of a multicenter trial of 105 cases comparing 133Xe and 99mTc-bicisate (ECD, neurolite) measured by SPECT on same day.
A multicenter study was performed in seven European centers comparing 99mTc-bicisate with 133Xe as a means of evaluating bicisate as a tracer of CBF distribution in humans. The same type of single photon emission computed tomography (SPECT) instrument (Tomomatic) was used in all centers. A total of 115 cases were collected, and of these 105 were considered technically adequate, comprising 18 normal subjects, 18 senile dementia, eight epilepsy, one brain tumor, eight chronic head trauma, and 52 stroke cases. As expected, bicisate gave better spatial resolution than Xe. Agreement between the results of the two methods was noted in 98 cases, but not in the remaining 7, all belonging to the stroke group. These seven all suffered from a subacute stroke (11-23 days after onset), and the disagreement in all cases consisted of bicisate showing low count rate in the area of the infarct and Xe a normal or elevated flow (luxury perfusion) as sign of spontaneous thrombolysis with reperfusion; in fact, these seven cases comprised all the reperfusion cases in the series. The results validate bicisate as a tracer of CBF in normal humans and in chronic brain diseases. Only in a subgroup of subacute stroke cases does bicisate not follow CBF, as it fails to show reperfusion hyperemia. This suggests the usefulness of bicisate in stroke cases, particularly in the subacute phase, where other SPECT methods often present difficulties due to reflow masking the size and the severity of the lesion.
Aged↗
99mTc-bicisate (neurolite) SPECT brain imaging and cognitive impairment in dementia of the Alzheimer type: a blinded read of image sets from a multicenter SPECT trial.
A blinded read of images obtained with 99mTc-bicisate and single photon emission computed tomography (SPECT) was conducted to determine if a relationship exists between the severity of abnormalities on SPECT brain images and the severity of cognitive impairment in patients with dementia of the Alzheimer type (DAT) and to examine the interreader agreement for visual reading of images in a multicenter SPECT study. Images for a total of 86 subjects were available for the blinded read. The images for 28 subjects were rated as noninterpretable due to technical inadequacies. Images for 58 subjects (45 DAT patients and 13 normal volunteers) from 10 SPECT centers were selected for further analyses. The severity of abnormality was rated as mild, moderate, or severe by three readers. In DAT patients, a significant negative correlation (p < 0.05) of Mini-Mental State Examination (MMSE) score with global severity of abnormality was noted for two of the three readers. A significant correlation (p < 0.05) between MMSE score and severity of abnormality was observed for all three readers for the posterior temporoparietal region. The blinded readers rated a median of 92.3% of normal volunteers' images as normal and a median of 82.2% of DAT patients' images as abnormal. For the regional severity of abnormality, the median percentage interrater agreement across all regions ranged from 95 to 100% in normal volunteers and from 81 to 98% in DAT patients. These results suggest that SPECT brain imaging with 99mTc-bicisate provides functional information about the severity of cognitive impairment in DAT patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Benzodiazepine receptor equilibrium constants for flumazenil and midazolam determined in humans with the single photon emission computer tomography tracer [123I]iomazenil.
This study is based on the steady state method for the calculation of Kd values recently described by Lassen (J. Cereb. Blood Flow Metab. 12 (1992), 709), in which a constant infusion of the examined nonradioactive ligand is used with a bolus injection of tracer. Eight volunteers were examined twice, once without receptor blockade and once with a constant degree of partial blockade of the benzodiazepine receptors by infusion of nonradioactive flumazenil (Lanexat) or midazolam (Dormicum). Single photon emission computer tomography and blood sampling were performed intermittently for 6 h after bolus injection of [123I]iomazenil. The tracer in plasma was determined by high-pressure liquid chromatography and also by a simple octanol extraction procedure. The free concentration of flumazenil and midazolam in plasma water averaged 52% and 3.5% of that in whole plasma. The Kd values for the entire cortical rim for flumazenil were 7.4, 10.0, 10.3 and 17.7 nmol/l plasma water and, for midazolam, 73, 76, 58 and 30 nmol/l plasma water. The variation exceeds random methodological error and is probably due to interindividual differences in receptor affinity. The Kd level of midazolam is considerably higher than expected from the results of in vitro studies.
Adolescent↗
Cerebral blood flow in patients with dementia of Alzheimer's type.
In the normal brain as well as in Alzheimer's disease (AD), regional cerebral blood flow (CBF) is coupled to metabolic demand and, therefore, changes in CBF reflect variations in neuronal metabolism. The use of radionuclide techniques, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT), provides an accurate assessment of regional functional activity, i.e., CBF and metabolism, and could be very helpful for the differential diagnosis of AD. This disease is characterized by a decrease in global CBF and metabolism. When found, a symmetric bi-parieto-temporal CBF reduction is highly diagnostic for AD, despite the fact that a similar CBF pattern could also be observed in other types of dementia. Many AD patients with parieto-temporal flow reduction also have a diffuse flow reduction in the frontal cortical areas, particularly in advanced stages of the disease. Lateral CBF asymmetry is also very frequent; speech disorders are highly characteristic of left-sided flow reduction, while visuospatial apraxia is dominating in the right-sided cases. In advanced and severe cases of AD, CBF and metabolism tend to be more uniformly reduced throughout the cortex, sparing only the primary visual and sensory-motor cortices. PET and SPECT measurement of brain perfusion and metabolism has added a new dimension to the knowledge of dementia disorders, with a better differential diagnosis between AD and other forms of dementia. The correlation with neuropsychological data has also given new insight into the disease.
Aging↗
Average blood flow and oxygen uptake in the human brain during resting wakefulness: a critical appraisal of the Kety-Schmidt technique.
The Kety-Schmidt technique can be regarded as the reference method for measurement of global average cerebral blood flow (average CBF) and global average cerebral metabolic rate of oxygen (average CMRO2). However, in the practical application of the method, diffusion equilibrium for inert gas tracer between the brain and its venous blood is not reached. As a consequence, normal values for CBF and CMRO2 of 54 ml 100 g-1 min-1 and 3.5 ml 100 g-1 min-1 obtained with the Kety-Schmidt technique are an overestimation of the true values. Using the Kety-Schmidt technique we have performed 57 measurements of CBF and CMRO2 during EEG-verified wakeful rest in young normal adults. In order to estimate the equilibrium values for CBF and CMRO2, a simple computer-based simulation model was employed to quantitate the systematic overestimation caused by incomplete tracer equilibrium. When correcting the measured data, we find that the true average values for CBF and CMRO2 in the healthy young adult are approximately 46 ml 100 g-1 min-1 and approximately 3.0 ml 100 g-1 min-1. Previous studies have suggested that some of the variation in CMRO2 values could be ascribed to differences in cerebral venous anatomy. However in the present study, no correlation between CMRO2 and cerebral venous anatomy as imaged by magnetic resonance angiography could be established. Our data show that the interindividual variation of CMRO2 is 11% (coefficient of variation).
Adult↗
Indomethacin abolishes cerebral blood flow increase in response to acetazolamide-induced extracellular acidosis: a mechanism for its effect on hypercapnia?
Indomethacin is known to attenuate quite markedly the increase in CBF during hypercapnia. Hypercapnia is, in all likelihood, mediated by the acid shift at the level of the smooth muscle cells of the cerebral arterioles. We therefore investigated the effect of indomethacin on the CBF increase caused by acetazolamide (Az), a drug that induces brain extracellular acidosis, which triggers its effect on CBF. We compared the results to the inhibitory effect of indomethacin on the CBF increase during hypercapnia. Indomethacin but not diclofenac, another potent cyclooxygenase inhibitor, was found to block almost completely the CBF increase caused by Az-induced extracellular acidosis or by CO2, but it did not influence the CBF increase produced by sodium nitroprusside or papaverine. The results suggest that indomethacin exerts its action on CO2 reactivity by a nonprostaglandin-mediated mechanism that directly interferes with the regulation of cerebrovascular tone mediated by extracellular pH.
Acetazolamide↗
Nitric oxide does not act as a mediator coupling cerebral blood flow to neural activity following somatosensory stimuli in rats.
The possible role of nitric oxide (NO) on vibrissa-stimulated increase of regional cerebral cerebral blood flow (rCBF) and cerebral metabolic rate of glucose (rCMRglu) was investigated in conscious Wistar rats by using an inhibitor of NO synthase, NG-nitro-L-arginine (NOLAG) at a concentration of 30 mg/kg. In vivo autoradiography distribution with 14C-iodoantipyrine and 14C-deoxyglucose in two separate series showed CBF of 174% of control and CMRglu of 196% of control in the primary sensory cortex opposite the stimulated side in saline treated control animals. Similar increases were found in NOLAG-treated animals. Furthermore, NOLAG did not change either basal CMRglu or CMRO2. The findings suggest, that NO is not involved in coupling flow to the increased metabolism accompanying physiological sensory stimuli.
Animals↗
Ischaemia-induced (symptomatic) migraine attacks may be more frequent than migraine-induced ischaemic insults.
Fifteen consecutive patients with a diagnostic problem of ischaemia-induced migraine with aura (symptomatic migraine) or migraine-associated ischaemia (migrainous infarction) were studied in order to elucidate the mechanisms. Three had a 1 month flurry of daily attacks of migraine auras with or without headache. A severe internal carotid stenosis/occlusion and reduced regional cerebral blood flow (rCBF) was demonstrated. Borderline ischaemia may thus prime the brain for developing migrainous aura with or without migraine (symptomatic migraine). Four patients had a combination of permanent deficits after the very first migraine attack, severe atherosclerosis, risk factors for stroke, high age and no family history of migraine. In these cases the evidence indicates that thromboembolic ischaemia had triggered an attack of migraine with aura (likely symptomatic migraine). Three young females presented long-lasting typical and severe idiopathic migraine with aura. Attack-associated rCBF reduction was likely to have caused permanent, mild, visual or somatosensory deficits (migrainous infarction). In five patients the relationship between migraine and stroke remained unresolved. It seems that ischaemia-induced migraine attacks may be more frequent than migraine-induced ischaemic insults. Therefore, migraine is not as strong a risk factor for stroke as indicated by the mere coincidence of the two disorders.
Adult↗
Reduced contralateral hemispheric flow measured by SPECT in cerebellar lesions: crossed cerebral diaschisis.
Four patients with clinical signs of cerebellar stroke were studied twice by SPECT using 99mTc-HMPAO as a tracer for cerebral blood flow (CBF). When first scanned 6 to 22 days after onset, all had a region of very low CBF in the symptomatic cerebellar hemisphere, and a mild to moderate CBF reduction (average 10%) in contralateral hemispheric cortex. In all four cases clinical signs of unilateral cerebellar dysfunction were still present when rescanned 1 to 4 months later and the relative CBF decrease in the contralateral cortex of the forebrain also remained. The basal ganglia contralateral to the cerebellar lesion CBF showed variable alterations. A relative CBF decrease was seen in upper part of basal ganglia in all four cases, but it was not a constant phenomenon. A relative CBF increase in both early and late SPECT scans was seen at low levels of neostriatum in two cases. The remote CBF changes in cerebellar stroke seen in the forebrain are probably caused by reduced or abolished cerebellar output. The term "Crossed Cerebral Diaschisis" may be used to describe these CBF changes that would appear to reflect both decreased and increased neuronal activity.
Aged↗
Middle cerebral artery blood velocity and cerebral blood flow and O2 uptake during dynamic exercise.
Results obtained by the 133Xe clearance method with external detectors and by transcranial Doppler sonography (TCD) suggest that dynamic exercise causes an increase of global average cerebral blood flow (CBF). These data are contradicted by earlier data obtained during less-well-defined conditions. To investigate this controversy, we applied the Kety-Schmidt technique to measure the global average levels of CBF and cerebral metabolic rate of oxygen (CMRO2) during rest and dynamic exercise. Simultaneously with the determination of CBF and CMRO2, we used TCD to determine mean maximal flow velocity in the middle cerebral artery (MCA Vmean). For values of CBF and MCA Vmean a correction for an observed small drop in arterial PCO2 was carried out. Baseline values for global CBF and CMRO2 were 50.7 and 3.63 ml.100 g-1.min-1, respectively. The same values were found during dynamic exercise, whereas a 22% (P < 0.0001) increase in MCA Vmean was observed. Hence, the exercise-induced increase in MCA Vmean is not a reflection of a proportional increase in CBF.
Adult↗
Hyperfixation of HMPAO in subacute ischemic stroke leading to spuriously high estimates of cerebral blood flow by SPECT.
Explore the source record for details and available documents.
Cerebrovascular Circulation↗
Neuroreceptor quantitation in vivo by the steady-state principle using constant infusion or bolus injection of radioactive tracers.
The approaches hitherto used for measuring the kinetic constants Kd and Bmax of neuroreceptors in vivo all violate the steady state of the system. This complicates the kinetic analysis as approximations must be made, introducing errors of unknown magnitude. The present study presents the theory for designing experiments in which the steady state is preserved. It is based on maintaining a constant degree of receptor binding (occupancy) throughout the experiment. This is achieved by administering by prolonged intravenous infusion the non-radioactive ligand one wishes to study. The fraction of receptors sites not occupied by the "cold" ligand is measured by using trace amounts of a radioactive ligand binding to the same receptor. A minimum of two studies at different occupanies must be performed. In this presentation it is proposed to make the second study at essentially zero receptor occupancy by administering the tracer alone. The pair of tracer studies, the one without and the other with infusion of cold ligand, allows calculation of the cold ligand's equilibrium dissociation constant Kd. In the special case when tracer and cold ligands are chemically identical, then Bmax can also be calculated. Two different modes of tracer administration can be used. If the tracer is also infused at a constant rate for a long time, then the occupancy of receptor sites by the cold ligand can be calculated by measuring the equilibrium tracer concentrations in brain and plasma. If the tracer is administered as an intravenous bolus injection, then the area under the brain and plasma radioactivity curves or compartmental analysis must be used.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effect of nitric oxide blockade by NG-nitro-L-arginine on cerebral blood flow response to changes in carbon dioxide tension.
The importance of nitric oxide (NO) for CBF variations associated with arterial carbon dioxide changes was investigated in halothane-anesthetized rats by using an inhibitor of nitric oxide synthase, NG-nitro-L-arginine (NOLAG). CBF was measured by intracarotid injection of 133Xe. In normocapnia, intracarotid infusion of 1.5, or 7.5, or 30 mg/kg NOLAG induced a dose-dependent increase of arterial blood pressure and a decrease of normocapnic CBF from 85 +/- 10 to 78 +/- 6, 64 +/- 5, and 52 +/- 5 ml 100 g-1 min-1, respectively. This effect lasted for at least 2 h. Raising PaCO2 from a control level of 40 to 68 mm Hg increased CBF to 230 +/- 27 ml 100 g-1 min-1, corresponding to a percentage CBF response (CO2 reactivity) of 3.7 +/- 0.6%/mm Hg PaCO2 in saline-treated rats. NOLAG attenuated this reactivity by 32, 49, and 51% at the three-dose levels. Hypercapnia combined with angiotensin to raise blood pressure to the same level as the highest dose of NOLAG did not affect the CBF response to hypercapnia. L-Arginine significantly prevented the effect of NOLAG on normocapnic CBF as well as blood pressure and also abolished its inhibitory effect on hypercapnic CBF. D-Arginine had no such effect. Decreasing PaCO2 to 20 mm Hg reduced control CBF to 46 +/- 3 ml 100 g-1 min-1 with no further reduction after NOLAG. Furthermore, NOLAG did not change the percentage CBF response to an extracellular acidosis induced by acetazolamide (50 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Increase of cerebral blood flow at high altitude: its possible relation to AMS.
CBF increases with acute hypoxia despite the opposing vasoconstrictor effects of the drop in pCO2 caused by hyperventilation. Maintaining normocapnia by adding CO2 the hypoxic CBF responsiveness about doubles. As we have shown recently by this test, the hypoxic CBF response is not blunted but rather somewhat sharpened over five days at almost 4000 meters of altitude. This, along with other evidence, shows that CBF does not in itself adapt to chronic hypoxia. Nevertheless, a decrease in CBF is seen over days at constant altitude primarily due to increase in the hematocrit. The cerebral vasodilatation cannot explain the usual (mild) form of AMS. But it may well be involved in the pathogenesis of the rare but severe cerebral form of AMS, as prolonged increased capillary pressure in vasodilated areas could lead to vasogenic cerebral edema.
Acute Disease↗
Is autoregulation of cerebral blood flow in rats influenced by nitro-L-arginine, a blocker of the synthesis of nitric oxide?
Explore the source record for details and available documents.
Animals↗