Imaging of dopamine transporters and D2 receptors in patients with Parkinson's disease and multiple system atrophy.

PURPOSE: The aim of this study was to ascertain whether combined presynaptic and postsynaptic dopaminergic single-photon emission computed tomography (SPECT) scanning is useful for differentiation between patients with idiopathic Parkinson's disease (IPD), patients with multiple system atrophy of the striatonigral type (MSA) and healthy subjects. METHODS: SPECT measurements of the dopamine transporter (DAT) were done with 123I-beta-CIT, while for determination of the dopamine D2-like receptors (D2), 123I-epidepride was used. Clinical evaluation and SPECT scans were carried out in 14 patients with IPD, eight patients with MSA and 11 healthy age-matched control subjects. RESULTS: Putaminal DAT binding was reduced to 32% of control values in IPD and to 19% of control values in MSA . Significantly higher striatal asymmetry in DAT binding was found in MSA than in controls, but IPD patients had significantly higher asymmetry than MSA patients. Striatal D2 binding did not differ significantly between patients and healthy controls but the ratio between caudate DAT and D2 binding was significantly higher in patients with IPD than in those with MSA, even when disease severity was taken into account. CONCLUSION: Patients with reduced striatal 123I-beta-CIT binding and a side-to-side difference greater than 15% are likely to suffer from IPD. Patients with reduced striatal 123I-beta-CIT binding and a side-to-side difference of between 5% and 15% are more likely to have MSA. 123I-epidepride SPECT measurements may add further diagnostic information, since the ratio between DAT and D2 receptor binding is significantly higher in IPD than in MSA.

Benzodiazepine receptor quantification in Huntington's disease with [(123)I]omazenil and SPECT.

OBJECTIVES: Increasing evidence suggests that metabolic changes predate neuronal death in Huntington's disease and emission tomography methods (PET and SPECT) have shown changes in glucose consumption and receptor function in early and possibly even presymptomatic disease. Because the GABA(A)-benzodiazepine receptor complex (BZR) is expressed on virtually all cerebral neurons BZR density images may be used to detect neuronal death. In this study the regional cerebral [(123)I]iomazenil binding to BZR was determined in patients with Huntington's disease and normal controls by a steady state method and SPECT. METHODS: Seven patients mildly to moderately affected by Huntington's disease and seven age matched controls were studied. Brain CT was performed on all subjects. In each subject two [(123)I]iomazenil-SPECT measurements were acquired-one with and one without infusion of flumazenil. The affinity constant of flumazenil (Kd) was calculated from the paired distribution volumes (DV) and the free plasma flumazenil concentration. The distribution volume of [(123)I]iomazenil in the unblocked condition (DV(0)) reflects the ratio between BZR density and Kd. RESULTS: Flumazenil Kd was similar in the Huntington's disease group and the control group (11.3 v 11.2 mM). For the Huntington's disease group a 31% reduction in striatal DV(0) (p=0.03) was found. In the cortical regions, DV(0) was similar in patients and in controls. In Huntington's disease, DV(0) correlated significantly with functional capacity (p=0.04) and chorea symptoms (p=0.02). The clinically least affected patients displayed DV(0)s within the range of those of the control group (19-35 ml/ml). CONCLUSIONS: The finding of an unchanged Kd of flumazenil in patients indicates that the BZR is functionally intact in Huntington's disease. That is, the reduction in DV(0) for BZR represents a selective decrease in the number of striatal BZRs. DV(0) significantly correlated with functional loss and [(123)I]iomazenil-SPECT could be an important tool for validation of the effect of future therapeutic strategies aimed at limiting oxidative stress and free radicals in Huntington's disease.

In vivo measurement of haloperidol affinity to dopamine D2/D3 receptors by [123I]IBZM and single photon emission computed tomography.

This study examines the feasibility of a steady-state bolus-integration method with the dopamine D2/D3 receptor single photon emission computer tomography (SPECT) tracer, [123I]IBZM, for determination of in vivo affinity of haloperidol. The nonspecific binding of [123I]IBZM was examined in the rat brain by infusion of haloperidol to plasma levels approximately 100 times the Kd level in man. In humans, Kd for haloperidol binding was measured in four healthy volunteers that were examined twice: once with partial dopamine D2/D3 receptor blockade obtained by a scheduled infusion of unlabeled haloperidol (0.7 mg total dosage), and once in an unblocked state. Blood sampling and SPECT were performed intermittently during 6 hours after intravenous [123I]IBZM bolus injection. Plasma [123I]IBZM was determined by octane extraction. Plasma haloperidol was determined by a radioimmunoassay, and plasma protein binding was determined by equilibrium dialysis. In humans, the striatal D2/D3 receptor occupancy was 0.27+/-0.085 and the in vivo Kd for haloperidol was 0.25+/-0.1 nmol/L, which is comparable to Kd values as obtained from in vitro studies. The authors conclude that steady-state [123I]IBZM SPECT studies allow for determination of dopamine D2/D3 receptor occupancy in striatum and in vivo measurement of drug affinity to striatal dopamine D2 and D3 receptors.

SPECT tracer [(123)I]IBZM has similar affinity to dopamine D2 and D3 receptors.

Emission tomography investigations of the pathophysiological involvement of the cerebral dopaminergic transmitter system in the living human brain relies heavily on a careful selection of the most suitable radioligand. In recent years, many clinical studies have employed [(123)I]IBZM in SPECT studies. The aim of the present study was to characterize the binding of IBZM to dopaminergic receptor subtypes as a means of elucidating which receptor subtypes are visualized and examined by [(123)I]IBZM. The affinity of IBZM for each of the major human dopamine receptors (D1, D2(short), D3, D4(4. 2), and D5 receptor) was determined by competitive radioligand binding assay using membranes prepared from clonal cell lines expressing the different subtypes. Radioligands with high affinity for the D1(A) and D5 receptors ([(3)H]SCH-23390), dopamine D2(short) and D4(4.2) receptors ([(3)H]Spiroperidol), and dopamine D3 receptor ([(3)H]7-OH-DPAT) were used to measure specific binding. Corresponding unlabeled displacing ligands for determination of nonspecific binding were employed. Assays were performed at 25 degrees C. These experiments show that for IBZM K(i) values were 1.6 nM for dopamine D2(s) receptors and 2.2 nM for dopamine D3 receptors. There was no binding of IBZM to D1(A), D5, or D4(4.2) receptors. In conclusion, when [(123)I]IBZM is used as SPECT tracer, the studies reflect dopaminergic D2 as well as D3 receptor binding.

Dopamine D(2) receptor quantification in extrastriatal brain regions using [(123)I]epidepride with bolus/infusion.

The iodinated benzamide epidepride, which shows a picomolar affinity binding to dopamine D(2) receptors, has been designed for in vivo studies using SPECT. The aim of the present study was to apply a steady-state condition by the bolus/infusion approach with [(123)I]epidepride for the quantification of striatal and extrastriatal dopamine D(2) receptors in humans. In this way the distribution volume of the tracer can be determined from a single SPECT image and one blood sample. Based on bolus experiments, an algorithm using conventional convolution arguments for prediction of the outcome of a bolus/infusion (B/I) experiment was applied. It was predicted that a B/I protocol with infusion of one-third of the initial bolus per hour would be appropriate. Steady-state conditions were attained in extrastriatal regions within 3-4 h but the infusion continued up to 7 h in order to minimize the significance of individual differences in plasma clearance and binding parameters. A steady-state condition, however, could not be attained in striatal brain regions using a B/I protocol of 20 h, even after 11 h. Under near steady-state conditions a striatal:cerebellar ratio of 23 was demonstrated. Epidepride has a unique signal-to-noise ratio compared to [(123)I]IBZM but present difficulties for steady-state measurements of striatal regions. The bolus/infusion approach is particularly feasible for quantification of the binding potential in extrastriatal regions.

No effect of insulin on glucose blood-brain barrier transport and cerebral metabolism in humans.

The effect of hyperinsulinemia on glucose blood-brain barrier (BBB) transport and cerebral metabolism (CMRglc) was studied using the intravenous double-indicator method and positron emission tomography using [18F]fluorodeoxyglucose as tracer (PET-FDG). Sixteen normal healthy control subjects (25 +/- 4 years old) were studied twice during a euglycemic and a euglycemic-hyperinsulinemic condition. Our hypothesis was that high physiologic levels of insulin did not affect the BBB transport or net metabolism of glucose. During insulin infusion, arterial plasma insulin levels increased from 48.5 to 499.4 pmol/l. The permeability-surface area products for glucose and FDG BBB transport obtained with the double-indicator method remained constant during hyperinsulinemia. Similarly using PET-FDG, no changes were observed in the unidirectional clearance of FDG from blood to brain. k2* (FDG transport from brain to blood) increased significantly by 15 and 18% (gray and white matter, respectively), and k4* (dephosphorylation of FDG) increased by 18%. The increase in k2* may be caused by insulin inducing a decrease in the available FDG brain pool. The increase in k4* may be related to an increased loss of labeled products during insulin fusion. Irrespective of these changes, CMRglc remained unchanged in all brain regions. We conclude that hyperinsulinemia within the normal physiologic range does not affect BBB glucose transport or net cerebral glucose metabolism.

Blood-brain barrier transport and protein binding of flumazenil and iomazenil in the rat: implications for neuroreceptor studies.

The calculated fraction of receptor ligands available for blood-brain barrier passage in vivo (f(avail)) may differ from in vitro (f(eq)) measurements. This study evaluates the protein-ligand interaction for iomazenil and flumazenil in rats by comparing f(eq) and f(avail). Repeated measurements of blood-brain barrier permeability for two benzodiazepine antagonists were performed in 44 rats by the double-indicator technique. Cerebral blood flow was measured by intracarotid Xe-injection. The apparent permeability-surface product (PSapp) was measured while CBF or bolus composition was changed. Comparison of PSapp obtained in the absence and presence of 5% albumin in the injectate yielded f(avail), whereas f(eq) was measured by equilibrium dialysis. Iomazenil and flumazenil f(avail) was 62% and 82%, respectively, whereas f(eq) was significantly lower, 42% and 61%. The PSapp for iomazenil and flumazenil increased significantly by 89% and 161% after relative CBF increases of 259% and 201%, respectively. The results demonstrate that application of f(eq) in neuroreceptor studies underestimates the plasma input function to the brain. Model simulations render possible that the differences between f(avail) and f(eq) as well as the effect of CBF on PSapp can be caused by capillary heterogeneity.

Cerebral glucose metabolism is decreased in white matter changes in patients with phenylketonuria.

Cerebral magnetic resonance imaging (MRI) has revealed white matter changes in patients with phenylketonuria (PKU), an inborn error of metabolism with increased plasma phenylalanine level. Because the significance of these lesions is unknown, this study was undertaken to determine whether glucose metabolism was depressed in cerebral white matter MRI changes in patients with PKU. Four patients with PKU and nine healthy volunteers with an average age of 23 y (range 19-26 y) and 23 y (range 20-27 y), respectively, were studied. The IQ of patients with PKU was between 58 and 97. Cerebral MRI and positron emission tomography images with 18F-deoxyglucose were obtained, and arteriovenous differences for oxygen and glucose as well as cerebral blood flow was measured simultaneously to determine global cerebral oxygen and glucose metabolism. Cerebral MRI revealed that all patients with PKU had white matter changes with characteristic localization. In patients with PKU, regional glucose metabolism was 36% lower in the anterior periventricular areas, 0.14 +/- 0.06 compared with 0.22 +/- 0.04 mumol.g-1.min-1 in controls (mean +/- SD, p < 0.05, Mann-Whitney). Further, the ratio between glucose metabolism in the affected white matter and the cortex was 14% lower in the patients, decreasing from 0.57 +/- 0.05 to 0.48 +/- 0.06 (p < 0.05). Global cerebral blood flow, oxygen and glucose consumption were similar in the two groups. In conclusion, regional glucose metabolism is lower in MRI-demonstrated white matter changes. In mildly intellectually impaired patients with PKU, global cerebral glucose and oxygen metabolism remain intact.

Neuroreceptor quantification in vivo by the steady state principle and [123I]iomazenil in rats.

A steady state method for neuroreceptor quantification in vivo in small laboratory animals is described, using [123I]iomazenil as tracer for the benzodiazepine receptor. The method was used for determination of the receptor equilibrium constant for a non-radioactive ligand, flumazenil, in rats and involved measurement of the nonspecific binding of [123I]iomazenil. Thirty-five animals were intravenously infused for 2 h with [123I]iomazenil and flumazenil in different proportions to obtain occupancies of the benzodiazepine receptor from close to 0 to about 99%. The nonspecific binding of iomazenil in brain tissue was calculated by an iterative procedure from the data for the highly blocked animals, and it was found to be 1.04 ml per ml plasma (n = 6). The mean cortical Kd of flumazenil was 21 +/- 11 nM (n = 19). The method is discussed with special reference to the problems of ascertaining steady state and nonspecific binding.

Tomographic cerebral blood flow measurement during carotid surgery.

OBJECTIVES: The aim of the study was to depict regional cerebral blood flow (rCBF) during carotid cross clamping using 99mTechnetium-hexamethylpropylene amine oxime (TcHMPAO). This tracer rapidly passes the blood-brain barrier and is retained for hours in the brain tissue. Injecting TcHMPAO during surgery and performing single photon emission computer tomography (SPECT) scanning shortly after the operation thereby pictures rCBF at the time of injection. DESIGN: Ongoing prospective study. SETTINGS: Departments of Vascular Surgery, Neurology and Anaesthesiology, University Hospital, Rigshospitalet, Copenhagen, Denmark. MATERIAL: 15 patients who during a period of 4 months underwent carotid endarterectomy. CHIEF OUTCOME MEASURES: Prior to surgery rCBF was determined using 133Xe and SPECT. Intraoperatively stump pressure was measured and a bolus of TcHMPAO was injected for later SPECT measurement. MAIN RESULTS: We found a significant correlation between stump pressure and enhancement of side-to-side asymmetry in rCBF due to carotid cross clamping. Pronounced variations were seen in which regions were deprived of perfusion during clamping. CONCLUSION: TcHMPAO allows tomographic assessment of CBF during carotid surgery. This method may serve as a reference tool in future research on intraoperative cerebral haemodynamics.

Brain extraction and distribution of 99mTc-bicisate in humans and in rats.

Blood-brain barrier (BBB) passage of the flow tracer ethylenediylbis-L-cystein diethylester (bicisate, ECD) was measured repeatedly in five patients by means of the intravenous (i.v.) double-indicator technique using 24Na+ as an intravascular cotracer. After i.v. injection, the arterial concentration curve of 99mTc-bicisate was delayed and dispersed compared with that of the intravascular cotracer, presumably due to lung retention of the flow tracer. The corrected cerebral venous output curves were fitted using a three-compartment model with four parameters. At resting cerebral blood flow (CBF) values, the unidirectional brain extraction was 0.57 +/- 0.05, the permeability-surface area product for passage from blood to brain (PS1) was 0.48 +/- 0.07 ml/g/min, and the distribution volume for bicisate was 0.74 +/- 0.20 (mean +/- SD). In a single patient, BBB transport after i.v. injection of bicisate was compared with that of a similar flow tracer, d,l-hexamethylpropyleneamine oxime (HM-PAO), and similar values were found for the two tracers. In 19 rats, the brain extraction of bicisate was measured by means of the intracarotid double-indicator technique. The brain extraction was measured at resting, decreased, and increased CBF values. Low CBF values were obtained by hyperventilation and high values by hypercapnia. The degree of backflux of tracer from brain to blood was evaluated by means of the three-compartment model and was found to be negligible in these experiments. The brain extraction was 0.70 +/- 0.1 and PS1 was 0.94 +/- 0.27 ml/g/min. During hypercapnia, CBF increased from 0.77 to 1.09 ml/g/min, leading to a significant decrease in brain extraction, from 0.70 to 0.56.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Thrombolytic therapy in acute ischemic stroke. A Danish pilot study.

BACKGROUND AND PURPOSE: In a feasibility and safety study of thrombolytic therapy in acute ischemic stroke, we explored the usefulness of measurements of regional cerebral blood flow. METHODS: Twenty-three patients with acute ischemic stroke were treated with 100 mg recombinant tissue plasminogen activator infused intravenously over 1 hour. Thrombolytic therapy was initiated 78 to 355 minutes after onset of symptoms. RESULTS: Angiography 16 to 24 hours after treatment in 17 patients showed patient intracranial arteries in 12, partial occlusion of the middle cerebral artery in 3, and total occlusion of the middle cerebral artery in 2. rCBF with 99mTc-hexamethylpropyleneamine oxime intravenously was measured 5 minutes before and within 24 hours after thrombolytic therapy in 12 patients. 10 of the 12 patients showed brain tissue reperfusion and 2, with angiographically documented middle cerebral artery occlusion, showed no reperfusion, thus documenting a relationship between reperfusion measured by regional cerebral blood flow and angiographic patency (P = .015). Three patients died. Patients who were reperfused within 24 hours (documented by repeated regional cerebral blood flow measurements) showed greater clinical improvement on the Scandinavian Stroke Scale the sooner their thrombolytic therapy was started and the more severe their neurological deficits. CONCLUSIONS: Acute cerebral ischemia can be documented by rCBF measurements without delay of thrombolytic therapy, and repeated rCBF measurements can reveal whether cerebral reperfusion has occurred. In our study, early reperfusion was associated with clinical improvement.

The effect of tirilazad mesylate (U74006F) on cerebral oxygen consumption, and reactivity of cerebral blood flow to carbon dioxide in healthy volunteers.

BACKGROUND: The 21-aminosteroids are a series of compounds designed to inhibit lipid peroxidation in the cell, and, as such, may have cerebral protective effects. The current study was performed to evaluate the effect of a 21-aminosteroid, tirilazad mesylate (U74006F), on cerebral blood flow, metabolism, and carbon dioxide reactivity. METHODS: Using a double-blind study design, eight volunteers received tirilazad mesylate, and eight others received only vehicle. The cerebral blood flow was measured by single photon emission computerized tomography using 133Xe inhalation in the resting condition at the beginning of the study and after infusion of tirilazad mesylate (1.5 mg/kg) or vehicle. Cerebral oxygen metabolism was calculated from the cerebral blood flow and the measured cerebral arteriovenous oxygen content difference. After both of the above cerebral blood flow measurements, arterial carbon dioxide tension was decreased by voluntary hyperventilation, and, later, increased by breathing an air/carbon dioxide mixture. The relative changes in cerebral blood flow induced by the PaCO2 variations were estimated from the changes in the arteriovenous oxygen content difference. RESULTS: Blood pressure, pulse rate, and PaCO2 were similar before and after the infusion of tirilazad mesylate in both groups, and there was no difference between the groups. The cerebral blood flow and oxygen metabolism did not change after the tirilazad mesylate infusion. The slope of the regression line of relative change of estimated cerebral blood flow and PaCO2 (regression coefficients in both groups, > 0.90) was unchanged after infusion. CONCLUSIONS: Tirilazad mesylate has no effect on cerebral blood flow, cerebral oxygen metabolism, or reactivity of cerebral blood flow to carbon dioxide in healthy volunteers.

Regional cerebral blood-flow measured by HMPAO and SPECT in a 5-year-old boy with Landau-Kleffner syndrome.

We present a 5-year-old boy with Landau-Kleffner syndrome, whose clinical manifestations were very similar to cases previously reported in the literature. CT and MRI scan failed to document any morphological abnormalities of his brain. However, high resolution rCBF imaging by HMPAO and SPECT demonstrated relatively low-flow areas in the left middle frontal gyrus and the right mesiotemporal/hippocampal region corresponding to the localization of EEG changes.

Thalamic infarcts: Effects on cerebral blood flow, metabolism, and neuropsychological function.

In four patients with thalamic infarcts causing severe neuropsychological deficits, regional cerebral blood flow (rCBF) was measured by single-photon emission computed tomography using (99m)Tc-d,l,-hexamethylpropyleneamine oxime as tracer. In one of these patients, cerebral glucose metabolism was measured by positron emission tomography using (18)F-fluorodeoxyglucose as tracer. Three patients had left paramedian thalamic infarcts, in one case combined with an infarction of the right cerebellar hemisphere, and one had bilateral paramedian and left anterior thalamic infarcts. Neuropsychological assessment revealed profound impairment of memory, verbal fluency, and abstract reasoning, as well as perseveration and varying degrees of dyscalculia and constructional apraxia in all patients. There were distinct personality changes and deficient judgment and insight. All four patients had reduced cortical rCBF in the left frontoparietal regions. In three cases, flow was also reduced in the left temporal lobe; they all presented with a fluent aphasia, which only partly remitted over time. Prosody and mimics were impaired only in the patient with bilateral thalamic infarction. In one of the patients with unilateral thalamic infarct extending into the mesencephalon, glucose metabolism was reduced in the ipsilateral frontal, temporal, and occipital regions. Thalamic infarcts can alter the activity in widespread functional systems of the brain and thus lead to extensive neuropsychological deficits.

The effect of ketanserin on cerebral blood flow and cerebrovascular CO2 reactivity in healthy volunteers.

The effect of the anti-hypertensive agent ketanserin on the cerebral blood flow (CBF) and the cerebrovascular CO2 reactivity was examined in 10 healthy volunteers. Ketanserin was administered as an intravenous bolus of 10 mg followed by an infusion of 6 mg/h. Before administration CBF was measured by single photon emission computerized tomography (SPECT) of inhaled 133Xenon. Then arterial CO2 tension was subsequently decreased by voluntary hyperventilation and increased by breathing an air/CO2 mixture. The relative changes in CBF induced by the changes in arterial CO2 tension were estimated by the cerebral arterio-venous oxygen content difference method. One hour following the start of ketanserin infusion the SPECT measurement and CO2 manipulations were repeated. The CO2 reactivity (expressed as the slope of the regression line of the linear relation between CBF and PaCO2), was unchanged, i.e. 3.2%/0.1 kPa before ketanserin and 4.1%/0.1 kPa during ketanserin, respectively. Using regression lines from a semi-logarithmic plot the CO2 reactivity was also unchanged 3.4%/0.1 kPa and 3.5%/0.1 kPa, respectively. Ketanserin did not change CBF. The cerebral oxygen metabolism (CMRO2) was decreased 19% one hour after the start of infusion of ketanserin. In conclusion administration of ketanserin in a clinically relevant dose to healthy volunteers does not change the regional CBF not the cerebrovascular CO2 reactivity, but a decrease in CMRO2 was observed. However further studies are needed to clarify whether ketanserin in fact has a depressing effect on CMRO2 or whether the different results are caused by methodological errors or stochastic variation.

[Extravasation of cytostatics. Example of a severe complication from the use of long-term central venous catheters]. / Ekstravasation af cytostatika. Eksempel på en alvorlig komplikation ved brug af centrale venøse langtidskatetre.

Completely implantable ports have become increasingly popular for venous access in the treatment of cancer. An uncommon but very serious complication is reported here: extravasation of a cytostatic agent secondary to a damaged Port-a-Cath catheter. Guidelines to be observed in implantation are recommended.

Cytostatic extravasation. A serious complication of long-term venous access.

Totally implantable ports have gained popularity as venous access in the treatment of cancer. A case is reported with an uncommon but very serious complication, i.e., cytostatic extravasation secondary to a broken implanted catheter. Guidelines for implantation and remedies are recommended.