Joël Aerts

Generation of rapid eye movements during paradoxical sleep in humans.

Although rapid eye movements (REMs) are a prominent feature of paradoxical sleep (PS), their origin and functional significance remain poorly understood in humans. In animals, including nonhuman primates, REMs during PS are closely related to the occurrence of the so-called PGO waves, i.e., prominent phasic activities recorded throughout the brain but predominantly and most easily in the pons (P), the lateral geniculate bodies (G), and the occipital cortex (O). Therefore, and because the evolution of species is parsimonious, a plausible hypothesis would be that during PS in humans, REMs are generated by mechanisms similar to PGO waves. Using positron emission tomography and iterative cerebral blood flow measurements by H(2)(15)O infusions, we predicted that the brain regions where the PGO waves are the most easily recorded in animals would be differentially more active in PS than in wakefulness, in relation with the density of the REM production [i.e., we looked for the condition (PS versus wakefulness) by performance (REM density) interaction]. Accordingly, we found a significant interaction effect in the right geniculate body and in the primary occipital cortex. The result supports the hypothesis of the existence of processes similar to PGO waves in humans, responsible for REM generation. The interest in the presence of PGO waves in humans is outstanding because the cellular processes involved in, or triggered by, PGO waves might favor brain plasticity during PS.

Brain function in the vegetative state.

Positron emission tomography (PET) techniques represent a useful tool to better understand the residual brain function in vegetative state patients. It has been shown that overall cerebral metabolic rates for glucose are massively reduced in this condition. However, the recovery of consciousness from vegetative state is not always associated with substantial changes in global metabolism. This finding led us to hypothesize that some vegetative patients are unconscious not just because of a global loss of neuronal function, but rather due to an altered activity in some critical brain regions and to the abolished functional connections between them. We used voxel-based Statistical Parametric Mapping (SPM) approaches to characterize the functional neuroanatomy of the vegetative state. The most dysfunctional brain regions were bilateral frontal and parieto-temporal associative cortices. Despite the metabolic impairment, external stimulation still induced a significant neuronal activation (i.e., change in blood flow) in vegetative patients as shown by both auditory click stimuli and noxious somatosensory stimuli. However, this activation was limited to primary cortices and dissociated from higher-order associative cortices, thought to be necessary for conscious perception. Finally, we demonstrated that vegetative patients have impaired functional connections between distant cortical areas and between the thalami and the cortex and, more importantly, that recovery of consciousness is paralleled by a restoration of this cortico-thalamo-cortical interaction.

Imaging a cognitive model of apraxia: the neural substrate of gesture-specific cognitive processes.

The present study aimed to ascertain the neuroanatomical basis of an influential neuropsychological model for upper limb apraxia [Rothi LJ, et al. The Neuropsychology of Action. 1997. Hove, UK: Psychology Press]. Regional cerebral blood flow was measured in healthy volunteers using H215O PET during performance of four tasks commonly used for testing upper limb apraxia, i.e., pantomime of familiar gestures on verbal command, imitation of familiar gestures, imitation of novel gestures, and an action‐semantic task that consisted in matching objects for functional use. We also re‐analysed data from a previous PET study in which we investigated the neural basis of the visual analysis of gestures. First, we found that two sets of discrete brain areas are predominantly engaged in the imitation of familiar and novel gestures, respectively. Segregated brain activation for novel gesture imitation concur with neuropsychological reports to support the hypothesis that knowledge about the organization of the human body mediates the transition from visual perception to motor execution when imitating novel gestures [Goldenberg Neuropsychologia 1995;33:63–72]. Second, conjunction analyses revealed distinctive neural bases for most of the gesture‐specific cognitive processes proposed in this cognitive model of upper limb apraxia. However, a functional analysis of brain imaging data suggested that one single memory store may be used for “to‐be‐perceived” and “to‐be‐produced” gestural representations, departing from Rothi et al.s proposal. Based on the above considerations, we suggest and discuss a revised model for upper limb apraxia that might best account for both brain imaging findings and neuropsychological dissociations reported in the apraxia literature. Hum. Brain Mapp. 21:119–142, 2004.

18F-fluoride PET/CT for assessing bone involvement in prostate and breast cancers

ObjectiveTo evaluate the accuracy of 18F-fluoride PET/computed tomography (CT) to detect bone metastases (BMs) in a breast and prostate cancer population, using magnetic resonance imaging (MRI) or thin-slice CT as a gold standard. MethodsWe have prospectively included 34 patients with breast (N=24) or prostate cancer (N=10) at high risk of BMs. Whole-body PET/CT (low-dose CT) and bone scintigraphy (BS) with single photon emission CT were obtained for all 34 patients and the results compared with a radiological gold standard. ResultsOut of the 386 foci detected by PET/CT, 219 (56.7%) could be verified by CT or MRI. Eighty-six additional foci were detected by BS (n=46) or seen only by CT (n=9), MRI (n=23), or both CT and MRI (n=8). The total number of verified lesions was therefore 274 (58.1%), including 119 (43.4%) benign and 155 (56.6%) BM. The sensitivity, specificity, and accuracy of 18F-fluoride PET/CT were 76, 84.2, and 80%, respectively. For BS, they were 44.8, 79.2, and 60%, respectively. Sensitivity significantly decreased for the lytic lesions. The accuracy of PET/CT was significantly superior to BS for pelvic and lumbar lesions. PET/CT provided a correct diagnosis (M+/M0) in 32 of 33 patients (one false positive) compared with 28 of 33 with BS (four false positive, one false positive). Conclusion 18F-fluoride PET/CT is significantly more accurate than BS for detecting BMs from breast and prostate cancers.

The role of lateral occipitotemporal junction and area MT/V5 in the visual analysis of upper-limb postures.

Humans, like numerous other species, strongly rely on the observation of gestures of other individuals in their everyday life. It is hypothesized that the visual processing of human gestures is sustained by a specific functional architecture, even at an early prelexical cognitive stage, different from that required for the processing of other visual entities. In the present PET study, the neural basis of visual gesture analysis was investigated with functional neuroimaging of brain activity during naming and orientation tasks performed on pictures of either static gestures (upper-limb postures) or tridimensional objects. To prevent automatic object-related cerebral activation during the visual processing of postures, only intransitive postures were selected, i. e., symbolic or meaningless postures which do not imply the handling of objects. Conversely, only intransitive objects which cannot be handled were selected to prevent gesture-related activation during their visual processing. Results clearly demonstrate a significant functional segregation between the processing of static intransitive postures and the processing of intransitive tridimensional objects. Visual processing of objects elicited mainly occipital and fusiform gyrus activity, while visual processing of postures strongly activated the lateral occipitotemporal junction, encroaching upon area MT/V5, involved in motion analysis. These findings suggest that the lateral occipitotemporal junction, working in association with area MT/V5, plays a prominent role in the high-level perceptual analysis of gesture, namely the construction of its visual representation, available for subsequent recognition or imitation.

PET/CT of Skull Base Meningiomas Using 2-18F-Fluoro-l-Tyrosine: Initial Report

Precise delineation of the shape of skull base meningiomas is critical for their treatment and follow-up but is often difficult using conventional imaging such as CT and MRI. We report our results with PET/CT and 2-18F-fluoro-l-tyrosine (18F-TYR), a marker of amino acid transport, as part of the yearly follow-up of irradiated patients. Methods: Eleven patients (mean age, 56.5 y) with skull base meningiomas (n = 13 lesions) previously irradiated were included. All patients received 300 MBq of 18F-TYR and were imaged after 30 min of uptake, using a dedicated PET/CT system. The images were first visually examined, and regions of interest (ROI) were then placed over the transaxial PET slice showing the highest uptake. Another ROI was placed over the normal parietal cortex. Tumor-to-cortex activity ratios were obtained by dividing the maximum pixel value in the tumor ROI by the maximum pixel value in the cortex ROI. The PET/CT images were compared with the MR images obtained as part of routine follow-up. Results: Accumulation of the tracer was higher in all meningiomas than in the surrounding tissue. The tumor-to-cortex activity ratio was 2.53 ± 0.35 (range, 1.3–6). Nonneoplastic tissue such as hyperemic cavernous sinus did not take up the radionuclide and was therefore easily distinguished from the meningioma. The 18F-TYR anomalies completely overlapped with the MR image in 54% of the tumors, extended beyond the MRI lesion in 38% of the tumors, and were smaller in 8% of the tumors. Conclusion: Meningiomas of the skull base are clearly visualized using 18F-TYR PET/CT, even after irradiation. In addition to MRI, 18F-TYR PET/CT images may contribute to the evaluation, delineation, and follow-up of these tumors.

[18F]p-MPPF: A Radiolabeled Antagonist for the Study of 5-HT1A Receptors with PET

Abstract This paper summarizes the present status of the researches conducted with [ 18 F]4-(2′-methoxyphenyl)-1-[2′-[ N -(2′′-pyridinyl)- p -fluorobenzamido]ethyl]-piperazine known as [ 18 F] p -MPPF, a new 5-HT 1A antagonist for the study of the serotonergic neurotransmission with positron emission tomography (PET). This includes chemistry, radiochemistry, animal data (rats, cats, and monkeys) with autoradiography and PET, human data with PET, toxicity, and metabolism.

Preclinical radiation dosimetry for the novel SV2A radiotracer [18F]UCB-H.

Background[18F]UCB-H was developed as a novel radiotracer with a high affinity for synaptic vesicle protein 2A, the binding site for the antiepileptic levetiracetam. The objectives of this study were to evaluate the radiation dosimetry of [18F]UCB-H in a preclinical trial and to determine the maximum injectable dose according to guidelines for human biomedical research. The radiation dosimetry was derived by organ harvesting and dynamic micro positron emission tomography (PET) imaging in mice, and the results of both methods were compared.MethodsTwenty-four male C57BL-6 mice were injected with 6.96 ± 0.81 MBq of [18F]UCB-H, and the biodistribution was determined by organ harvesting at 2, 5, 10, 30, 60, and 120 min (n = 4 for each time point). Dynamic microPET imaging was performed on five male C57BL-6 mice after the injection of 9.19 ± 3.40 MBq of [18F]UCB-H. A theoretical dynamic bladder model was applied to simulate urinary excretion. Human radiation dose estimates were derived from animal data using the International Commission on Radiological Protection 103 tissue weighting factors.ResultsBased on organ harvesting, the urinary bladder wall, liver and brain received the highest radiation dose with a resulting effective dose of 1.88E-02 mSv/MBq. Based on dynamic imaging an effective dose of 1.86E-02 mSv/MBq was calculated, with the urinary bladder wall and liver (brain was not in the imaging field of view) receiving the highest radiation.ConclusionsThis first preclinical dosimetry study of [18F]UCB-H showed that the tracer meets the standard criteria for radiation exposure in clinical studies. The dose-limiting organ based on US Food and Drug Administration (FDA) and European guidelines was the urinary bladder wall for FDA and the effective dose for Europe with a maximum injectable single dose of approximately 325 MBq was calculated. Although microPET imaging showed significant deviations from organ harvesting, the Pearson’s correlation coefficient between radiation dosimetry derived by either method was 0.9666.

Evaluation of 18F-UCB-H as a Novel PET Tracer for Synaptic Vesicle Protein 2A in the Brain

Synaptic vesicle protein 2 isoforms are critical for proper nervous system function and are involved in vesicle trafficking. The synaptic vesicle protein 2A (SV2A) isoform has been identified as the binding site of the antiepileptic levetiracetam (LEV), making it an interesting therapeutic target for epilepsy. 18F-UCB-H is a novel PET imaging agent with a nanomolar affinity for human SV2A. Methods: Preclinical PET studies were performed with isoflurane-anesthetized rats. The arterial input function was measured with an arteriovenous shunt and a β-microprobe system. 18F-UCB-H was injected intravenously (bolus of 140 ± 20 MBq). Results: Brain uptake of 18F-UCB-H was high, matching the expected homogeneous distribution of SV2A. The distribution volume (Vt) for 18F-UCB-H was calculated with Logan graphic analysis, and the effect of LEV pretreatment on Vt was measured. In control animals the whole-brain Vt was 9.76 ± 0.52 mL/cm3 (mean ± SD; n = 4; test–retest), and the reproducibility in test–retest studies was 10.4% ± 6.5% (mean ± SD). The uptake of 18F-UCB-H was dose dependently blocked by pretreatment with LEV (0.1–100 mg/kg intravenously). Conclusion: Our results indicated that 18F-UCB-H is a suitable radiotracer for the imaging of SV2A in vivo. To our knowledge, this is the first PET tracer for the in vivo quantification of SV2A. The necessary steps for the implementation of 18F-UCB-H production under good manufacturing practice conditions and the first human studies are being planned.

Epimerization study on [18F]FDG produced by an alkaline hydrolysis on solid support under stringent conditions

Since 1998, routine [18F]FDG syntheses are being carried out by alkaline hydrolysis on a solid support, i.e. the labeled intermediate is trapped on a tC18 solid phase extraction cartridge, purified and finally hydrolyzed within the cartridge, at room temperature, using sodium hydroxide. The present study demonstrated that no epimerization of [18F]FDG to [18F]FDM occurs even when 12 N NaOH is used and when the hydrolysis time is extended up to 1 h. The alkaline hydrolysis on solid support appears to be a simple method leading to [18F]FDG with high purity.