Sven Valind

Simultaneous Intracerebral Microdialysis and Positron Emission Tomography in the Detection of Ischemia in Patients with Subarachnoid Hemorrhage

Intracerebral microdialysis (MD) was applied in patients with subarachnoid hemorrhage. The regional CBF, the CMRO2, and oxygen extraction ratio (OER) were measured with simultaneous positron emission tomography (PET). The aim was to directly correlate alterations in dialysate levels of energy-related metabolites (lactate, lactate/pyruvate ratio, hypoxanthine) and excitatory amino acids (EAAs) (glutamate and aspartate) to the energy state in the MD probe region as determined by PET. Regional ischemia was defined according to Heiss et al. and Lassen (Heiss et al., 1992; Lassen, 1966). Whole-brain ischemia was considered present when the OER for the whole brain exceeded the mean whole-brain OER + 2 SD of six reference patients. In general, the presence of whole-brain ischemia and/or regional ischemia within the region of the MD probe was associated with increased levels of energy-related metabolites and EAAs retrieved by MD. Increased levels of energy-related metabolites and EAAs were only occasionally seen when PET did not show any signs of ischemia or when signs of regional ischemia were found remote from the MD probe region. Thus, the energy-related metabolites and EAAs may be used as extracellular “markers” of ischemia. PET may be of use in defining critical ischemic regions (tissue at risk) where the MD probe can be inserted for- chemical monitoring.

NMDA‐Receptor Activity Visualized with (S)‐[N‐Methyl‐11C]Ketamine and Positron Emission Tomography in Patients with Medial Temporal Lobe Epilepsy

Summary: Purpose: To determine whether neurochemical activation of the N‐methyl‐D‐aspartate (NMDA) receptor‐gated ion channel shows quantitative changes, measured as binding of 11C‐labeled (S)‐[N‐methyl]ketamine, in patients with medial temporal lobe epilepsy (MTLE).

Brain networks affected by synchronized sleep visualized by positron emission tomography.

Nineteen lightly sleep-deprived healthy volunteers were examined with H215O and positron emission tomography (PET). Scanning was performed during wakefulness and after the subjects had fallen asleep. Sleep stage was graded retrospectively from electroencephalogram (EEG) recordings, and scans were divided into two groups: wakefulness or synchronized sleep. Global flow was quantified, revealing no difference between sleep and wakefulness. A pixel-by-pixel—blocked one-way analysis of variance (ANOVA) was performed after correcting for differences in anatomy and global flow. The sum of squares of the z-score distribution showed a highly significant (P < 0.00001) omnibus difference between sleep and wakefulness. The z-score images indicated decreased flow in the thalamus and the frontal and parietal association cortices and increased flow in the cerebellum during sleep. A principal component (PC) analysis was performed on data after correction for global flow and block effects, and a multivariate analysis of variance (MANOVA) on all PC scores revealed significant (P = 0.00004) differences between sleep and wakefulness. Principal components 2 and 5 correlated to sleep and revealed distinct networks consisting of PC 2, cerebellum and frontal and parietal association cortices, and PC 5, thalamus.

Deposition and Disposition of [11C]Zanamivir Following Administration as an Intranasal Spray

ObjectiveThis study used positron emission tomography (PET) to investigate the deposition and disposition of zanamivir administered as a nasal spray.DesignThis was an open-label single-dose study in healthy volunteers.Study participantsSix healthy male volunteers, aged 19 to 33 years (mean age 25 years) with a bodyweight of 65 to 94kg (mean bodyweight 76kg), took part in the study.InterventionsEach participant received by nasal spray zanamivir 6.4mg mixed with, on average, 2.5 MBq of [11C]zanamivir. The amount of radioactivity was recorded sequentially in 5 different sectors of the body, starting with a short dynamic sequence over the nasal passage. Each of the regions was examined 1 to 4 times at different times after inhalation. The duration of the examination was 90 minutes. During this time, multiple blood samples were taken for analysis of radioactivity in whole blood. Serum samples for pharmacokinetic determinations were collected for 8 hours after administration.ResultsImmediately after administration, about 90% of the drug was deposited in the nasal passage, decreasing to 48% at 90 minutes after administration. Less than 2% was detected in the lower respiratory tract. The major elimination route was via the oesophagus to the stomach. Approximately 2% of the dose was absorbed; the median maximum drug concentration in serum was 15 μg/L, and occurred around 1.75 hours after inhalation.ConclusionsThe major deposition site for zanamivir administered by nasal inhalation is the nasal passage; half of the drug remains there for at least 1.5 hours after administration. PET seems to be an excellent tool for this type of kinetic study, allowing imaging and measurements of inhaled drugs with high quantitative accuracy and good spacial resolution.

Neuroimaging study in autosomal dominant cerebellar ataxia, deafness, and narcolepsy

Article abstract Four patients affected with autosomal dominant cerebellar ataxia, deafness, and narcolepsy underwent brain CT and MRI. Radiologic findings were supratentorial atrophy (more pronounced than infratentorial atrophy), pronounced dilatation of the third ventricle, low T2 signal intensity in the basal ganglia, loss of cerebral cortex–white matter differentiation, and periventricular high-signal rims. 2-[18F]Fluoro-2-deoxy-D-glucose PET was done with one patient, without specific findings. Genetic analyses excluded SCA-1, SCA-2, SCA-3, SCA-6, SCA-7, DRPLA, and huntingtin gene mutations.

Synthesis of [1-11C], [2-11C], [1-11C](2H3) and [2-11C](2H3)acetate for in vivo studies of myocardium using PET

Four isotopically-labelled acetates ([1-11C], [2-11C], [1-11C](2H3) and [2-11C](2H3)acetate) were synthesized and used in positron emission tomography (PET) studies of pig myocardium. The [1-11C]acetates were synthesized by carboxylation of the appropriate 1H or 2H methyl Grignard reagents immobilized on a C2 solid phase extraction column (SPE). Purification by reverse-phase HPLC, resulted in 35-45% decay-corrected radiochemical yield with a total synthesis time of 25 min, and a radiochemical purity higher than 99%. The [2-11C]acetates were synthesized by carboxylation of 11C-labelled 1H or 2H methyl lithium. Purification as above resulted in 35-55% decay-corrected radiochemical yield with a total synthesis time of 30 min, and a radiochemical purity higher than 99%. Position-specific labelling was assessed by 13C-labelling and NMR. Multiple isotopic labelling by the combination of position-specific 11C-labelling and 2H substitution, has the potential to highlight different aspects of a complex biochemical system using a selected set of tracers in comparative PET studies. An illustration of this principle is given using acetate, where citric acid cycle metabolism results in a position-specific kinetic for the 11C-label, and deuteration opens up the possibility for the proton-abstracting processes within the citric acid cycle to be assessed.

Activation PET scanning in pretreatment evaluation of patients with cerebral tumours or vascular lesions in or close to the sensorimotor cortex

SummaryTreatment of tumours and vascular lesions in or close to eloquent cortex may inflict neurological deficits. Intra-operative mapping procedures have been used for many decades in efforts to minimize neurological sequelae. The possibility for non-invasive preoperative brain mapping has emerged with the advent of positron emission tomography (PET).In this paper we report on 11 patients with a tumour or vascular lesion in or close to the sensorimotor (10 patients) or visual cortex (one patient). The patients were subjected to activation PET scanning by means of vibrotactile or visual stimulation. The results show that in most of the patients the important relation between the lesion and the sensorimotor cortex could be determined. The patient with a lesion in the occipital lobe had involvement of the entire visual cortex as judged by comparison with activated areas on the nonlesion side.

Synthesis of fatty acids specifically labelled with 11C in various positions, including 2H substitution, for in vivo studies of myocardium using PET

Fatty acids were labelled with 11C in several positions by reacting [11C]carbon dioxide with the appropriate Grignard reagent or by reacting a alpha, omega-bis-(bromo magnesium) alkane with a 11C-labelled alkyl iodide followed by a reaction with carbon dioxide. The methyl and methylene 11C-labelled fatty acids were obtained in 12-36% (decay corrected) radiochemical yield within 45-65 min, and with radiochemical purities higher than 96%. Perdeuterated alpha, omega-dibromo hexane, decane and tetradecane were synthesized from dimethylacetylene dicarboxylate by means of a Raney-nickel reduction in D2O, Kolbe electrolysis and LAD reduction. The use of multiple isotopic labelling by the combination of position specific 11C labelling and 2H substitution, has the potential to highlight different aspects of a complex biochemical system by PET. This principle is illustrated by results of the kinetics of different types of 11C label of dodecanoic acid and the corresponding moieties of acetate. The combination of tracers allows the kinetics of beta-oxidation of middle length carbon chain fatty acids and citric acid cycle metabolism to be separately assured, whilst deuteration of the tracers opens the possibility of highlighting the kinetics of the proton extraction processes reflecting rate limiting steps.

A positron emission tomography study of cerebral blood flow and oxygen metabolism in healthy male volunteers anaesthetized with eltanolone

Background: The effects of eltanolone anaesthesia in humans on regional cerebral blood flow, regional cerebral metabolic rate of oxygen and oxygen extraction ratio were to be evaluated using positron emission tomography (PET).

Is PET a Tool for Drug Evaluation

The determination of the relation between administered dose and clinical outcome is one of the most important tasks in the development of a new drug. The ultimate goal of human pharmacology is thus to create an understanding of the events occurring from the moment of administration, via adsorption of the drug, distribution in different organs, metabolism and excretion, responses in target organs and biochemical effector systems to the effects of the whole organism and to clinical outcome. Usually this information is obscured by limitations of the present in vivo measurement techniques which in humans is primarily limited to evaluations of plasma pharmacokinetics. The important intermediate steps in the chain of events from administration to clinical outcome have to be deduced from models by analysing plasma pharmacokinetics, combined with extrapolations from animal experiments.