Management of radioactive waste gases from PET radiopharmaceutical synthesis using cost effective capture systems integrated with a cyclotron safety system.

The emphasis on the reduction of gaseous radioactive effluent associated with PET radiochemistry laboratories has increased. Various radioactive gas capture strategies have been employed historically including expensive automated compression systems. We have implemented a new cost-effective strategy employing gas capture bags with electronic feedback that are integrated with the cyclotron safety system. Our strategy is suitable for multiple automated 18F radiosynthesis modules and individual automated 11C radiosynthesis modules. We describe novel gas capture systems that minimize the risk of human error and are routinely used in our facility.

Heteronuclear NMR spectroscopic investigations of hydrogen bonding in 2-(benzo[d]thiazole-2'-yl)-N-alkylanilines.

The 2-(benzo[d]thiazole-2'-yl)-N-alkylanilines have previously revealed the presence of a strong intramolecular hydrogen bond. This in turn gives rise to a more complicated multiplet for the protons attached to the carbon adjacent to the amino group. This intramolecular hydrogen bond was investigated by a deuterium exchange experiment using heteronuclear NMR spectroscopy (1H, 13C, 15N and 2H). We observed changes in the multiplet structure and chemical shifts providing further evidence that the deuterium replaces the hydrogen in the intramolecular hydrogen bond. A time course study of the D2O exchange confirmed the presence of a strong hydrogen bond. The comparison of the structures obtained by X-ray crystallography showed a very small difference in planarity between the two-substituted and four-substituted amino compounds. In both the cases, the phenyl ring is not absolutely coplanar with the thiazole unit. The existence of this intramolecular hydrogen bond in 2-(benzo[d]thiazole-2'-yl)-N-alkylanilines was further confirmed by single crystal X-ray crystallography.

Synthesis, characterization and (11) C-radiolabeling of aminophenyl benzothiazoles: structural effects on the alkylation of amino group.

Several aminophenyl benzothiazoles were prepared with a view to using them as amyloid binding agents for imaging ß-amyloid in Alzheimer's disease. These precursors were radiolabeled with (11) C-positron-emitting radioisotope using an automated synthesizer and selected radiolabeled compounds were further purified by HPLC. Our results demonstrate that changes in structure have a major influence on the radioactive yield and the ease with which the radiolabel can be introduced. Aminophenyl benzothiazoles with an attached isopropyl group resisted dialkylation perhaps due to steric hindrance caused by this group. Straight chain attachment of methyl, ethyl, butyl, and crotyl groups in the structure decreased the radiochemical yield. Notably, the o-aminophenyl benzothiazole derivatives were difficult to alkylate despite stringent experimental conditions. This reactivity difference is attributed to the hydrogen bonding characteristics of the o-amino group with the nitrogen atom of the thiazole ring.

Synthesis and characterization of 1- and 2-cinnamoyloxyacetonaphthones.

The synthesis of 1- and 2-cinnamoyloxyacetonaphthones was achieved in one step using hydroxyl acetonaphthones and substituted cinnamic acids in the presence of a catalytic amount of phosphoroxychloride. Structural characterization was accomplished using high-resolution nuclear magnetic resonance (NMR) spectroscopy. Chemical shifts of the compounds were compared and the change in the chemical shifts relative to electron-donating and -withdrawing groups is presented. Introduction of a thiophene ring instead of phenyl-substituted analogs caused shielding of the olefinic proton.

Hippocampal volume and depression: insights from epilepsy surgery.

BACKGROUND: Major depression is common after epilepsy surgery. It has previously been suggested that surgical removal of limbic system structures such as the hippocampus may contribute to this comorbidity. Recent magnetic resonance imaging studies have found smaller hippocampal volumes in depressed patients in comparison with controls. AIMS: The current study examined whether preoperative hippocampal volumes were associated with depression experienced after epilepsy surgery. Patients undergoing mesial (n = 26) and non-mesial (n = 16) temporal lobe resections were assessed preoperatively, and for 1 year postoperatively. Assessment included a clinical interview and the Beck Depression Inventory. Hippocampal volumes were measured on the preoperative T1-weighted magnetic resonance imaging scans of the patients and 41 neurologically normal controls. RESULTS: A similar proportion of mesial and non-mesial temporal patients had a preoperative history of major depression. Postoperatively, 42% of mesial and 19% of non-mesial temporal patients were depressed. There was no relationship between hippocampal volume and preoperative depression in either group. Depression after surgery was associated with significantly smaller hippocampal volumes contralateral to the resection in the mesial temporal group (p = 0.005). This effect was seen in mesial temporal patients who developed de novo depression (p = 0.006). Hippocampal volume was unrelated to postoperative depression in the non-mesial group. CONCLUSION: This study highlights the role of neurobiological factors in the development of postoperative depression. These initial findings have implications for understanding depression following epilepsy surgery as well as the pathogenesis of depression more generally.

Radiolabeling of protected tryptophan with [18F]fluoromethyl tosylate: Formation of [18F]fluoromethyl ester of tryptophan instead of 1-N-[18F]fluoromethyl tryptophan methylester.

The reaction of [18F]fluoromethyl tosylate with methyl(tert-butoxycarbonyl)-l-tryptophanate results in formation the O-alkylated ester of the tryptophan instead of alkylation of the indole nitrogen of tryptophan as initially anticipated. Treatment of protected tryptophan with NaH in dimethyl formamide (DMF) along with [18F]fluoromethyl tosylate at 130°C results in the formation of [18F]fluoromethyl(tert-butoxycarbonyl)-l-tryptophanate. Preferential formation of the O-alkylated product is postulated to be due to the hydrolysis of the ester. Confirmation of the O-alkylation was obtained by synthesizing the [19F]fluoromethyl(tert-butoxycarbonyl)-l-tryptophanate insitu and examining its NMR characteristics using multiple NMR techniques. Similar results were also obtained when reacting Boc-tryptophan-N-carboxyanhydride precursor with fluoromethyl tosylate.

Effect of levetiracetam on cortical excitability: a transcranial magnetic stimulation study.

BACKGROUND AND PURPOSE: We studied the effect of levetiracetam (LEV), an anticonvulsant with a novel mechanism of action, on cortical excitability, measured using transcranial magnetic stimulation (TMS). For this purpose, 38 healthy volunteers were assessed in two TMS sessions, before and after an oral dose of 3000 mg LEV. METHODS: Resting motor threshold (RMT), intracortical facilitation (ICF) and intracortical inhibition (ICI), cortical silent period (CSP) threshold and duration and motor-evoked potential (MEP) amplitude were calculated. RESULTS: After treatment with LEV, RMT was increased (mean +/- SD: 63 +/- 14% of the maximum stimulator output) compared with baseline (58 +/- 11%). CSP threshold was decreased after LEV (54 +/- 10%; baseline, 57 +/- 11%). CSP duration was increased after LEV (116 +/- 37 ms; baseline: 102 +/- 33 ms). LEV did not affect ICF or ICI or mean MEP amplitude significantly. CONCLUSIONS: Our results indicate that LEV modulates some aspects of cortical excitability. Whereas the increase in the RMT most probably reflects the effect of LEV on ion channel activity, effects on the CSP might represent a modulation of GABA receptors at cortical and spinal level.

Challenges in the automated synthesis of [18F]-1-fluoroethyl tryptophan: Formation of both O- and N-alkylated products.

[18F]Fluoroethyl tosylate was synthesized using an automated "Synthra" module using ethylene di-tosylate and [18F]fluoride/K222/K2CO3 in acetonitrile. [18F]Fluoroethyl tosylate was purified by semi-preparative HPLC followed by reformulation using a C18 Sep-Pak cartridge and eluted with DMF. Using this [18F]fluoroethyl tosylate, we attempted to alkylate protected tryptophan aiming to obtain the N-[18F]fluoroethyl-t-Boc-tryptophan methyl ester. Initial attempts resulted in the formation of the O-alkylated, rather than N-alkylated product. Manual removal of the cartridge from the automated module, followed by an extended drying of the cartridge under high flow nitrogen, was required to form the desired N-alkylated product. This demonstrates that the drying process in automated modules requires modification for sensitive N-alkylation of compounds and may be essential for compounds like tryptophan methyl ester that have multiple potential sites of alkylation in their chemical structure.

Topography and temporal evolution of hypoxic viable tissue identified by 18F-fluoromisonidazole positron emission tomography in humans after ischemic stroke.

BACKGROUND AND PURPOSE: We sought to characterize the spatial and temporal evolution of human cerebral infarction. Using a novel method of quantitatively mapping the distribution of hypoxic viable tissue identified by 18F-fluoromisonidazole (18F-FMISO) PET relative to the final infarct, we determined its evolution and spatial topography in human stroke. METHODS: Patients with acute middle cerebral artery territory stroke were imaged with 18F-FMISO PET (n=19; <6 hours, 4; 6 to 16 hours, 4; 16 to 24 hours, 5; 24 to 48 hours, 6). The hypoxic volume (HV) comprised voxels with significant (P<0.05; >1 mL) uptake on statistical parametric mapping compared with 15 age-matched controls. Central, peripheral, and external zones of the corresponding infarct on the anatomically coregistered delayed CT were defined according to voxel distance from the infarct center and subdivided into 24 regions by coronal, sagittal, and axial planes. Maps ("penumbragrams") displaying the percentage of HV in each region were generated for each time epoch. RESULTS: Higher HV was observed in the central region of the infarct in patients studied within 6 hours of onset (analysis of covariance [ANCOVA]; P<0.05) compared with those studied later, in whom the HV was mainly in the periphery or external to the infarct. HV was maximal in the superior, mesial, and posterior regions of the infarct (ANCOVA; P<0.05). CONCLUSIONS: These observations suggest that infarct expansion occurs at the expense of hypoxic tissue from the center to the periphery of the ischemic region in humans, similar to that seen in experimental animal models. These findings have important pathophysiological and therapeutic implications.

Brief vibrotactile stimulation does not increase cortical oxygen consumption when measured by single inhalation of positron emitting oxygen.

Vibrotactile stimulation of the hand elicits no increase in oxygen consumption commensurate with the increase in blood flow measured in human sensory cortex. To test the hypothesis that previous failures to detect a proportionate increase in oxygen consumption could be an artefact of the sequential bolus, or three-step, method used to measure this parameter in the human brain in vivo, the authors compared the measurements with the results of a novel single bolus, or one-step, method of measuring oxygen consumption. The time of completion of the three-step method was 40 to 50 minutes, whereas the one-step method lasted only 3 minutes. The baseline whole-brain oxygen consumption averaged 185 +/- 32 micromol hg(-1) min(-1) by the three-step method and 153 +/- 15 micromol hg(-1) min(-1) by the one-step method. Vibrotactile stimulation did not elicit a significant increase in oxygen consumption measured by either method. This finding rejects the hypothesis that failure to detect an increase of oxygen consumption could be an artefact caused by limitations of the method used previously. Conversely, it also rejects the hypothesis that observations of an increase of oxygen consumption by the new method are artefacts caused by limitations of the one-step method.

Oxygen consumption of cerebral cortex fails to increase during continued vibrotactile stimulation.

The coupling of oxidative metabolism to the blood flow of the sensory motor hand area is uncertain. The authors tested the hypothesis that continued vibrotactile stimulation ultimately must lead to increased oxygen consumption consumption. Twenty-two healthy right-handed young volunteers underwent positron emission tomography (PET) with the [(15)O]water bolus injection method to measure water clearance (K1H2O an index of blood flow (CBF), and with the [(15)O]oxygen bolus inhalation method to measure CMR(O2). The CMR(O2) was measured 30 seconds and 20 minutes after onset of intermittent (1 second on, 1 second off) vibrotactile stimulation (110 Hz) and compared with baseline measurements without stimulation. The K1H2O and CMR(O2) changes (delta K1H2O and delta CMR(O2)) were determined using intersubject averaging, together with magnetic resonance imaging based stereotaxic registration technique. The K1H2O increase was 21 +/- 4% and 12 +/- 4% at 30 seconds and 20 minutes after onset of stimulation, respectively. No significant increase of CMR(O2) was found until 30 minutes after the onset of stimulation. The authors conclude that blood flow and oxidative metabolism undergo uncoupling during sustained phasic stimulation of the sensory hand area. Therefore, neuronal activity stimulated in this manner does not rely on significantly increased oxidative phosphorylation.

Cerebral [15O]water clearance in humans determined by PET: I. Theory and normal values.

When used to measure blood flow in the brain, water leaves a residue in the vascular bed that influences the estimation of blood flow by current methods. To assess the magnitude of this influence, we developed a two-compartment model of blood flow with separate parameters for transport and vascular distribution of brain water. Maps of the water clearance, K1 into brain tissue, separated from the circulation by a measurably resistant blood-brain barrier (BBB), were generated by time-weighted integration. Depending on the validity of the assumptions underlying the two-compartment model presented here, the maps revealed a significant overestimation of the clearance of water when the vascular residue was ignored. Maps of Vo, the estimate of the apparent vascular distribution volume of tracer H2(15)O, clearly revealed major cerebral arteries. Thus, we claim that the accumulation of radioactive water in brain tissue also reflects the volume of the arterial vascular bed of the brain.

Cerebral [15O] water clearance in humans determined by positron emission tomography: II. Vascular responses to vibrotactile stimulation.

When used to measure blood flow, water leaves a residue in the vascular bed, which may contribute to the calculation of increased blood flow during functional activation of brain tissue. To assess the magnitude of this contribution with the two-compartment positron emission tomography (PET) method, we mapped the water clearance (K1) of the brain as an index of cerebral blood flow (CBF) and the apparent vascular distribution of nonextracted H2 15O (Vo). The latter map represented mainly the cerebral arterial and arteriolar volume. We also prepared subtraction maps (delta K1, delta Vo) of the response to vibrotactile stimulation of the fingertips of the right hand of six normal volunteers. Using magnetic resonance (MR) images of all subjects, the data were rendered into Talairach's stereotaxic coordinates and the averaged subtraction images (activation minus baseline) merged with the corresponding averaged MRI image. The delta K1 map revealed the expected response in the primary sensory hand area; the delta Vo response was located about 13 mm more anteriorly, close to the central fissure, most likely reflecting changes of the arteries feeding the primary sensory hand area. We conclude that cerebral perfusion and cerebrovascular responses to vibrotactile stimulation may occur in disparate locations that can be identified separately by using the two-compartment method.

L-arginine infusion increases basal but not activated cerebral blood flow in humans.

Nitric oxide is a potent vasodilator. Infusion of its precursor, L-arginine, results in increased cerebral blood flow (CBF) in experimental animals. We examined the effects of L-arginine infusion on CBF in humans using positron emission tomography and the quantitative H2(15)O method. Six subjects received 500 ml of 0.9% NaCl solution, and six subjects received an infusion of L-arginine (16.7 mg/kg/min; 500 mg/kg). Before and after the i.v. infusion, paired CBF measurements were performed at baseline and with vibrotactile stimulation of the right hand. In scans performed without vibrotactile stimulation, mean whole-brain CBF increased from 34.9 +/- 3.7 ml 100 g-1 min-1 to 38.2 +/- 4.4 ml 100 g-1 min-1. (9.5%; p < 0.005) after L-arginine infusion. The temporal pattern of CBF changes differed from that of plasma growth hormone and insulin levels and of arterial pH. In contrast, in the saline group, mean whole-brain CBF did not change significantly (35.8 +/- 5.9 ml 100 g-1 min-1 to 35.9 +/- 6.4 ml 100 g-1 min-1; 0.3%). Vibrotactile stimulation produced significant focal increases in CBF, which were unaffected by L-arginine infusion. L-arginine infusion was associated with an increase in plasma L-citrulline, a byproduct of nitric oxide synthesis.

Idiopathic generalized epilepsy of adolescence: are the syndromes clinically distinct?

Juvenile myoclonic epilepsy, juvenile absence epilepsy, and epilepsy with generalized tonic-clonic seizures (GTCS) on awakening are the three syndromes of idiopathic generalized epilepsy of adolescent onset currently included in the classification of epilepsy syndromes of the International League Against Epilepsy (ILAE). Although they differ in their predominant seizure types, the syndromes share several clinical features, thus giving rise to questions of phenotypic overlap and purity. We studied the clinical features of 101 patients with idiopathic generalized epilepsy beginning in adolescence. A standardized interview was used to elucidate seizure phenomenology, precipitants, frequency, and response to treatment. Groups defined by seizure type were compared and their similarities examined. The group with myoclonic but not absence seizures (21 patients) corresponded to the ILAE syndrome of juvenile myoclonic epilepsy, whereas those with absences but not myoclonus (37 patients) resembled juvenile absence epilepsy. Twenty-six patients shared the features of juvenile myoclonic epilepsy and juvenile absence epilepsy. Epilepsy with GTCS on awakening was not a specific syndromic entity; 10 patients had this seizure type alone. Seven patients were without a syndromic diagnosis. In these patients only GTCS occurred, but neither on awakening nor in the evening period of relaxation. We conclude that whilst syndromes of idiopathic generalized epilepsy of adolescence can be recognized, the current classification does not include all patients. In addition, the boundaries between the syndromes are indistinct, suggesting underlying neurobiological, possibly genetic, relationships.

Cortical hyperexcitability in progressive myoclonus epilepsy: a study with transcranial magnetic stimulation.

In progressive myoclonus epilepsy (PME), responses to afferent input are frequently abnormal. It is unclear whether the abnormality lies at the cortical, subcortical, or segmental level. To obtain evidence for an exaggerated effect on motor cortical excitability, we used peripheral nerve and transcranial magnetic stimulation in controls and subjects with idiopathic generalized epilepsy and PME. Mean threshold intensity was higher in those with idiopathic generalized epilepsy and PME than in controls, probably as a result of anticonvulsant treatment. A long-latency response to peripheral stimulation and an exaggerated facilitatory effect of peripheral stimulation on the motor evoked potential was present in subjects with PME. Latency differences between the late responses in the upper and lower limbs provided evidence against a segmental reflex and implicated rapidly conducting fibers in the spinal cord. Both the late response and the facilitatory effect had onset latencies consistent with a transcortical pathway, suggesting an exaggerated effect of afferent input on motor cortical excitability in PME.

Lateralizing value of peri-ictal headache: A study of 100 patients with partial epilepsy.

To determine the lateralizing value of peri-ictal headache, the authors conducted a standardized interview of 100 patients with partial epilepsy, 60 with temporal lobe epilepsy (TLE) and 40 with extratemporal epilepsy (ETE). Peri-ictal headache occurred in 47 of 100 (47%) patients. Peri-ictal headache was more likely to be ipsilateral to the seizure onset in TLE (27 of 30 = 90%) than in ETE (two of 17 = 12%; p< 0.001). For both groups, peri-ictal headache usually conformed to the diagnostic criteria for common migraine (18 of 30 = 60% in TLE; 7 of 17 = 41% in ETE).

Entorhinal cortex in temporal lobe epilepsy: a quantitative MRI study.

BACKGROUND: The entorhinal cortex (EC) is a distinct anatomic and functional region of the anterior parahippocampal gyrus, which plays a role in seizure generation and propagation in temporal lobe epilepsy (TLE). In tissue resected from TLE patients, cell loss in the EC has been described. OBJECTIVES: To develop a standardized protocol for identifying the anatomic boundaries of the EC using high-resolution MRI and to examine morphologic changes of the EC in TLE. METHODS: We performed T1-weighted MRIs in 20 patients (7 males) with TLE (mean age 34 years) and 18 normal controls (mean age 26 years). Eleven patients had a left and 9 a right epileptic focus as defined by history, video-EEG, and surgical outcome. The volumes of the EC, the hippocampus, and the amygdala were measured using a standardized MRI protocol. Analysis of variance (ANOVA) was used to examine the effect of seizure focus lateralization and hemisphere on these volumes. An asymmetry ratio [A (%) = 100 x (R-L)/(R+L)/2] was also compared between groups using ANOVA. RESULTS: In normal controls the volume of the right EC was 1,247 +/- 127 mm3 (mean +/- standard deviation), and that of the left EC was 1,215 +/- 135 mm3 (p > 0.05). We found a bilateral reduction in the volume of the EC in TLE patients compared with controls (p < 0.05). Examination of the asymmetry ratios showed that the reduction in volume of the EC was greater ipsilateral to the epileptic focus (p < 0.05). The volumes of the hippocampus and the amygdala were smaller on the side of the focus in TLE patients compared with controls (p < 0.05). CONCLUSIONS: With a standardized protocol for the quantitative assessment of the EC, patients with unilateral TLE show bilateral reduction in the volume of the EC. However, this reduction is more severe ipsilateral to the epileptic focus.

Late-onset drop attacks in temporal lobe epilepsy: a reevaluation of the concept of temporal lobe syncope.

We report the clinical, radiologic, and EEG features of six patients with temporal lobe drop attacks (TLDA), all of whom underwent temporal resection. Postoperative follow-up of at least 1 year was available in all. TLDA were never the first manifestation but followed the onset of epilepsy after a long delay ranging from 7 to 43 years (mean, 24.4 years). Seizures were of unilateral temporal origin. In one patient, stereo EEG recording of TLDA showed rapid spread of the ictal discharge away from the temporal lobe in less than 1 second. Postoperatively, three patients were seizure free; one has had no TLDA but experiences sporadic auras; another, despite a reduction of more than 50%, continues to have complex partial seizures and TLDA; and the sixth has had sporadic secondarily generalized seizures upon reduction of antiepileptic medication. In conclusion, drop attacks may occur in temporal lobe epilepsy, usually long after the onset of epilepsy. They lead to increased disability and suggest a rapid spread of the ictal discharge and possible involvement of the pontine reticular formation rather than the presence of bitemporal foci or an extratemporal origin.

Dystonia, clinical lateralization, and regional blood flow changes in temporal lobe seizures.

We analyzed the lateralizing value of ictal dystonia and head-turning in temporal lobe epilepsy, and sought the biologic basis of these clinical signs by studying the regional changes in perfusion with ictal single-photon emission computed tomography (SPECT). We identified unilateral temporal lobe epilepsy in 40 of 42 patients undergoing evaluation for temporal lobe surgery, and with ictal SPECT all 40 showed striking hyperperfusion of the epileptogenic temporal lobe. Twenty-five of the 40 patients showed unilateral or predominantly unilateral upper limb dystonia, which was opposite the epileptic temporal lobe in all cases. Analysis of regional count ratios in cases with ictal dystonia, compared with those without, showed significant changes only in the basal ganglia. Specifically, we found that ictal dystonia was associated with a relative increase in perfusion of the basal ganglia opposite the dystonic limb. Although we found 26 cases with head-turning, the sign was of no lateralizing value, even when only those with major or "tonic" versions (n = 11) were analyzed. Slight increases in cortical blood flow on the side opposite the direction of version were associated with head-turning, irrespective of the side of seizure focus. In clinical practice, ictal SPECT is a highly accurate aid in the lateralization of temporal lobe foci, in addition to providing a new method to investigate the pathophysiology of clinical signs in focal seizures.