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OBJECTIVE: Neutrophilic inflammation plays a key role in the pathogenesis of acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). Positron emission tomography (PET) with [F]-fluoro-2-deoxy-d-glucose (FDG) can be used to image cellular metabolism that, during lung inflammatory processes, likely reflects neutrophils activity. The aim of this study was to assess the magnitude and regional distribution of inflammatory metabolic activity in the lungs of patients with ALI/ARDS by PET with FDG. DESIGN:: Prospective clinical investigation. PATIENTS:: Ten patients with ALI/ARDS; four spontaneously breathing and two mechanically ventilated subjects, without known lung disease, served as controls. INTERVENTIONS:: In each individual we performed an FDG PET/computed tomography of the thorax. MEASUREMENTS AND MAIN RESULTS:: FDG cellular influx rate constant (Ki) was computed for the imaged lung field and for regions of interest, grouping voxels with similar density. In all patients with ALI/ARDS, Ki was higher than in controls, also after accounting for the increased lung density. Ki values differed greatly among patients, but in all patients Ki of the normally aerated regions was much higher (2- to 24-fold) than in controls. Whereas in some patients the highest Ki values corresponded to regions with the lowest aeration, in others these regions had lower Ki than normally and mildly hypoaerated regions. CONCLUSION:: In patients with ALI/ARDS, undergoing mechanical ventilation since days, the metabolic activity of the lungs is markedly increased across the entire lung density spectrum. The intensity of this activation and its regional distribution, however, vary widely within and between patients.

Not all conceivable grammars are realized within human languages. Rules based on rigid distances, in which a certain word must occur at a fixed distance from another word, are never found in grammars of human languages. Distances between words are specified in terms of relative, non-rigid positions. The left inferior frontal gyrus (IFG) (Broca's area) has been found to be involved in the computation of non-rigid but not of rigid syntax in the language domain. A fundamental question is therefore whether the neural activity underlying this non-rigid architecture is language-specific, given that analogous structural properties can be found in other cognitive domains. Using event-related functional magnetic resonance imaging (fMRI) in sixteen healthy native speakers of Italian, we measured brain activity for the acquisition of rigid and non-rigid syntax in the visuo-spatial domain. The data of the present experiment were formally compared with those of a previous experiment, in which there was a symmetrical distinction between rigid and non-rigid syntax in the language domain. Both in the visuo-spatial and in the language domain, the acquisition of non-rigid syntax, but not the acquisition of rigid syntax, activated Brodmann Area 44 of the left IFG. This domain-independent effect was specifically modulated by performance improvement. Thus, in the human brain, one single "grammar without words" serves different higher cognitive functions.

There are several lines of evidence, the majority indirect, suggesting that changes in serotonergic or dopaminergic neurotransmission may contribute to the pathogenesis of obsessive-compulsive disorder (OCD). We evaluated the co-occurrence of serotonergic and dopaminergic dysfunctions in OCD subjects, all drug-naive, with no co-morbidity and homogeneous for symptoms. Each subject underwent two positron emission tomography (PET) scans to measure in vivo both serotonin (5-HT2A) and dopamine (D-2) receptor distribution. For this, we used [C-11]MDL and [C-11] Raclopride, highly selective antagonists of 5-HT2A and D-2 receptors, respectively. The comparison with a control group was carried out using both voxel-wise (SPM2) and regions of interest (ROI) approaches. There was a significant reduction of 5-HT2A receptor availability in frontal polar, dorsolateral, and medial frontal cortex, as well as in parietal and temporal associative cortex of OCD patients. We also found a significant correlation between 5-HT2A receptor availability in orbito-frontal and dorsolateral frontal cortex and clinical severity, suggesting a specific role for serotonin in determining the OCD symptoms. There was also a significant reduction of [C-11]Raclopride uptake in the whole striatum, particularly in the ventral portion, possibly reflecting endogenous dopaminergic hyperactivity. The co-existence of serotonergic and dopaminergic dysfunction in the same homogeneous group of drug-naive OCD patients provides in vivo evidence for the complex molecular mechanisms of OCD, and represents the basis for further studies on the effect of therapeutic agents with specific modulatory effects on these neurotransmission systems. (c) 2008 Elsevier Inc. All rights reserved.

BACKGROUND AND PURPOSE: Image-guided helical tomotherapy (HT) is a new modality for delivering intensity modulated radiation therapy (IMRT) with helical irradiation: the slip ring continuously rotates while the couch moves into the bore. The radiation source (Linac, 6MV) is collimated into a fan beam and modulated by means of a binary multileaf collimator (MLC). A xenon detector array, opposite the radiation source, allows a megavoltage-CT (MVCT) acquisition of patient images for set-up verification. The aim of this paper is to report the results of a two-year quality control (QC) program for the physical and dosimetric characterization of an HT unit installed at our Institute and clinically activated in November 2004, in order to monitor and verify the stability and the reliability of this promising radiation treatment unit. MATERIALS AND METHODS: Conventional Linac acceptance protocols (ATP) and QC protocols were adapted to HT with the addition of specific items reflecting important differences between the two irradiation modalities. QC tests can be summarized as: (a) mechanical and geometrical characterization of the system's components: evaluation of alignment among radiation source-gantry rotation plan-jaws-MLC-MVCT; (b) treatment beam configuration in static condition: depth dose curves (PDD) and profiles, output factors, output reproducibility and linearity; (c) dynamic component characterization: accuracy and reproducibility of MLC positioning; rotational output reproducibility and linearity, leaf latency, couch movement constancy; (d) gantry-couch and MLC-gantry synchronization; and (e) MVCT image quality. Peculiar periodicity specific tolerance and action levels were defined. Ionization chambers (Exradin A1SL 0.056cc), films (XOmat-V/EDR2), water and solid water phantoms were used to perform quality assurance measurements. RESULTS: Over a two-year period the final average output variation after possible beam output adjustment was -0.2+/-1% for the static condition and equal to 0+/-1% for the rotational condition: around 98% of the collected output data was within the action level compared to 94% if no beam output adjustment was considered. An average energy variation of -0.4+/-0.4% was found. The daily absolute dose verification of IMRT plans showed a dose reproducibility of -0.5+/-1.2% and -0.4+/-2.2%, for low and high dose gradient regions, respectively. Source-jaws-MLC and MVCT alignment results and jaw and leaf positioning accuracy were +/-1mm. Couch-gantry-MLC synchrony tests showed good stability level (+/-2mm). CONCLUSIONS: QC results indicated good reproducibility of all HT mechanical-dosimetric performance.

BACKGROUND AND PURPOSE: To investigate the impact of Helical Tomotherapy (HT) upon the dose distribution when compared to our routinely delivered 3D conformal radiotherapy (CRT) in the case of patients affected by stage III non-small-cell lung cancer (NSCLC). MATERIAL AND METHODS: Thirteen stage III inoperable NSCLC patients were scheduled to receive 61.2-70.2Gy, 1.8Gy/fraction. Two treatment techniques (HT and CRT) were considered, and in the case of CRT the dose calculation was performed using both the pencil beam (PB) and Anisotropic Analytical Algorithm (AAA) available on the Varian Eclipse planning system. Dose volume constraints for PTV coverage and OAR sparing were assessed for the HT inverse planning with the highest priority upon PTV coverage and spinal cord sparing. The three plans were compared in terms of dose-volume histograms (DVHs) and normal tissue complication probability (NTCP). A statistical analysis was performed using non-parametric Wilcoxon matched pairs tests. RESULTS: In CRT the use of a less accurate algorithm (PB) decreased the monitor unit number by 2.4%. HT significantly improved dose homogeneity within PTV compared with CRT_AAA. For lung parenchyma V20-V40 were lower with HT, corresponding to a decrease of 7% in the risk of radiation pneumonitis. The volume of the heart and esophagus irradiated to >45-60Gy were reduced using HT plans. For eight PTs with an esophagus-PTV overlap >5%, HT significantly reduced both late and acute esophageal complication probability. CONCLUSIONS: Our findings obtained in stage III NSCLC patients underline that HT guarantees an important sparing of lungs and esophagus, thus HT has the potential to improve therapeutic ratio, when compared with CRT, by means of dose escalation and/or combined treatment strategy. In CRT of locally advanced lung cancers, the use of a more advanced algorithm would give significantly better modeling of target dose and coverage.

BACKGROUND: Previous reports have shown that higher education is associated with more severe brain pathology in patients with Alzheimer disease (AD), suggesting that these individuals have a functional reserve provided by education, which masks the clinical expression of a higher degree of neurodegeneration. It is unknown if a similar reserve mechanism exists in patients with amnestic mild cognitive impairment (aMCI). The aim of this study was to assess the impact of education and occupation on brain glucose metabolism (rCMRglc) measured with FDG-PET in aMCI and in a very large sample of subjects with probable AD (pAD). METHODS: A total of 242 patients with pAD, 72 with aMCI, and 144 healthy controls participated in the study. At follow-up, 21 subjects with aMCI progressed to AD. A regression analysis was conducted (SPM2), with education and occupation as independent variables, and rCMRglc as dependent variable, adjusting for demographic data, global cognitive status, and neuropsychological scores. RESULTS: The analysis showed a significant association between higher education/occupation and lower rCMRglc in posterior temporoparietal cortex and precuneus in pAD and aMCI converters, and no correlation in aMCI nonconverters and healthy controls. This means that, when submitted to FDG-PET for diagnostic evaluation, pAD and aMCI converters with higher education/occupation had, for comparable cognitive impairment, a more severe rCMRglc reduction than the ones with lower education/occupation. CONCLUSIONS: This study suggests that education and occupation may be proxies for brain functional reserve, reducing the severity and delaying the clinical expression of Alzheimer disease (AD) pathology. The results in aMCI converters suggest that functional reserve is already at play in the predementia phase of AD.

Purpose The aims of this study were to compare CT with PET/CT results in patients with suspected ovarian cancer recurrence and to assess the impact of the PET/CT findings on their clinical management. Methods Thirty-two consecutive patients with suspected ovarian cancer recurrence were retrospectively included in the study. Abdominal contrast-enhanced CT and PET/CT with [18F]FDG, in addition to conventional follow-up, were performed in all 32 patients. After the comparison between CT and PET/CT results, based on clinical reports, changes in the clinical management of patients (intermodality changes) due to PET/CT information were analysed. Results Twenty of the 32 patients were positive at CT (62.5%) versus 29 (90.6%) at PET/CT. Intermodality changes in management, i.e. use of a different treatment modality, after PET/CT examination were indicated in 14/32 (44%) patients. In particular, before PET/CT study, the planned management was as follows: wait-and-see in 7/32 (22%), further instrumental examinations in 4/32 (12%), chemotherapy in 10/32 (31%), diagnostic surgical treatment in 6/32 (19%) and surgical treatment in the remaining 5/32 (16%). After PET/CT study, wait-and-see was indicated in 1/32 (3%), further instrumental examinations in 7/32 (22%), chemotherapy in 16/32 (50%), diagnostic surgical treatment in 2/32 (6%) and surgical treatment in the remaining 6/32 (19%). Conclusion Integrated PET/CT could detect tumour relapse in a higher percentage of patients than could CT. A change in the clinical management was observed in 44% of cases when PET/CT information was added to conventional follow-up findings.

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BACKGROUND AND PURPOSE: To investigate the usefulness of vesicourethral anastomotic biopsy (VUBx) in patients who are candidates for salvage radiotherapy (SalvRT) after radical prostatectomy (RRP). MATERIAL AND METHODS: From 1992 to 2001, 98 patients with a PSA failure (PSAf) after RRP underwent SalvRT to the prostatic bed (median dose 70Gy). In 50/98 patients the VUBx was positive, in 26 negative; 22 patients underwent SalvRT without a prior VUBx. The prognostic impact on biochemical disease-free survival (bNEDs) of histologic confirmation of the local failure was evaluated retrospectively. RESULTS: In the 40 patients with pre-RT PSA0.9ng/mL, no additional prognostic information derived from the VUBx, while, for higher PSA values, a positive histology resulted as a covariate independently predictive of post-RT outcome (5-year bNEDs: 74% vs 42% in the 35 and 23 patients with a positive or negative/not performed VUBx, respectively, P=.03), together with pT, pre-RT PSA 1.5ng/mL, and PSA doubling time. CONCLUSIONS: In case of PSAf after RRP, VUBx before SalvRT seems unnecessary for PSA0.9ng/mL. For higher values, a positive VUBx seems to always justify a SalvRT, which may not be recommendable, given the nonnegligible risk of an already micrometastatic disease, if the biopsy results are negative.

AIMS AND BACKGROUND: Mediastinal elective node irradiation (ENI) in patients with non-small cell lung cancer candidate to radical radiotherapy is controversial. In this study, the impact of co-registered [18F]fluorodeoxyglucose-positron emission tomography (PET) and standard computed tomography (CT) on definition of target volumes and toxicity parameters was evaluated, by comparison with standard CT-based simulation with and without ENI. METHODS: CT-based gross tumor volume (GTVCT) was first contoured by a single observer without knowledge of PET results. Subsequently, the integrated GTV based on PET/CT coregistered images (GTVPET/CT) was defined. Each patient was planned according to three different treatment techniques: 1) radiotherapy with ENI using the CT data set alone (ENI plan); 2) radiotherapy without ENI using the CT data set alone (no ENI plan); 3) radiotherapy without ENI using PET/CT fusion data set (PET plan). Rival plans were compared for each patient with respect to dose to the normal tissues (spinal cord, healthy lungs, heart and esophagus). RESULTS: The addition of PET-modified TNM staging in 10/21 enrolled patients (48%); 3/21 were shifted to palliative treatment due to detection of metastatic disease or large tumor not amenable to high-dose radiotherapy. In 7/18 (39%) patients treated with radical radiotherapy, a significant (> or =25%) change in volume between GTVCT and GTVPET/CT was observed. For all the organs at risk, ENI plans had dose values significantly greater than no-ENI and PET plans. Comparing no ENI and PET plans, no statistically significant difference was observed, except for maximum point dose to the spinal cord Dmax, which was significantly lower in PET plans. Notably, even in patients in whom PET/CT planning resulted in an increased GTV, toxicity parameters were fairly acceptable, and always more favorable than with ENI plans. CONCLUSIONS: Our study suggests that [18F]-fluorodeoxyglucose-PET should be integrated in no-ENI techniques, as it improves target volume delineation without a major increase in predicted toxicity.

PURPOSE: To explore the potential of helical tomotherapy (HT) in the treatment of nasopharynx cancer. PATIENTS AND METHODS: Six T1-4 N1-3 patients were considered. A simultaneous integrated boost (SIB) technique was planned with inversely optimized conventional intensity-modulated radiotherapy (IMRT; dynamic multileaf collimator using the Eclipse-Helios Varian system) and HT. The prescribed (median) doses were 54 Gy, 61.5 Gy, and 64.5 Gy delivered in 30 fractions to PTV1 (planning target volume), PTV2, and PTV3, respectively. The same constraints for PTV coverage and for parotids, spinal cord, mandible, optic structures, and brain stem were followed in both modalities. The planner also tried to reduce the dose to other structures (mucosae outside PTV1, larynx, esophagus, inner ear, thyroid, brain, lungs, submental connective tissue, bony structures) as much as possible. RESULTS: The fraction of PTV receiving > 95% of the prescribed dose (V95%) increased from 97.6% and 94.3% (IMRT) to 99.6% and 97% (HT) for PTV1 and PTV3, respectively (p < 0.05); median dose to parotids decreased from 30.1 Gy for IMRT to 25.0 Gy for HT (p < 0.05). Significant gains (p < 0.05) were found for most organs at risk (OARs): mucosae (V30 decreased from 44 cm(3) [IMRT] to 18 cm(3) [HT]); larynx (V30: 25 cm(3) vs. 11 cm(3)); thyroid (mean dose: 48.7 Gy vs. 41.5 Gy); esophagus (V45: 4 cm(3) vs. 1 cm(3)); brain stem (D1%: 45.1 Gy vs. 37.7 Gy). CONCLUSION: HT improves the homogeneity of dose distribution within PTV and PTV coverage together with a significantly greater sparing of OARs compared to linac five-field IMRT.

PURPOSE: In order to explore the potential of helical Tomotherapy in the treatment of head and neck cancers (HNC), a planning study comparing our routinely delivered IMRT technique (dynamic MLC Varian 600CD Linac, inversely optimised by the Helios/Eclipse system) against two different Tomotherapy planning approaches was performed. MATERIALS AND METHODS: In the first Tomotherapy plan (TOMO-a), we merely applied the same constraints used for the IMRT-Linac technique; in the second one (TOMO-b), we tried to stress the sparing of parotids and mandible while keeping PTV coverage and spinal cord Dmax similar to their values in the TOMO-a plan. Five patients with locally advanced oropharinx (n=3), hypopharinx (n=1) and larynx (n=1) cancer were considered. For each patient, CTV1 including neck nodes and the tumour was defined and was expanded with a margin of 0.5 cm (PTV1); then, CTV2 including high risk nodes and CTV3 including only T were defined and the corresponding PTV2/PTV3 were defined by a 0.5 cm expansion. IMRT and Tomotherapy planning were optimised to deliver 54 Gy in 30 fractions on PTV1 and 16.2 Gy in 9 fractions on PTV3; in the case a PTV2 was defined, 15 Gy were concomitantly delivered while delivering 16.2 Gy on PTV3. Separated plans for the two phases (Phase 1: first 30 fractions; Phase 2: last 9 fractions) were compared in terms of dose-volume histograms (DVH) and dose statistics on PTVs and OARs. RESULTS: When considering Phase 1, Tomotherapy improved the homogeneity of the dose distribution within PTV1 while delivering the same prescribed dose (assessed to be the median dose to PTV): the fraction of PTV1 receiving more than 95% of the prescribed dose (V95%) increased from 90% (IMRT) to 96-97% for Tomotherapy plans. Dmax within PTV1 decreased from 60.3 Gy (IMRT) to 57.4 Gy (TOMO-a) and 58.7 Gy (TOMO-b). Spinal cord Dmax decreased from 31.6 Gy (IMRT) to 26.5 Gy (TOMO-a) and 24.6 Gy (TOMO-b). No attempts to further reduce spinal cord Dmax were done. Mean dose to the parotids decreased from 26.1 Gy (IMRT) to 25.1 Gy (TOMO-a) and 20.8 Gy (TOMO-b). Mandible was significantly better spared with Tomotherapy: mean dose decreased from 34.9 Gy (IMRT) to 34.0 Gy (TOMO-a) and 30.7 Gy (TOMO-b).When considering phase 2, the average gains (TOMO-b vs IMRT) were more modest and depended on the location of PTV2/PTV3. CONCLUSIONS: Preliminary findings obtained in a sequential approach for HNC suggest that Tomotherapy has the potential to significantly improve the therapeutic ratio with respect to a conventional IMRT delivery method.

We have developed a method that needs only the computed tomography (CT) indicator box to coregister positron emission tomography (PET) images and integrates this information with magnetic resonance imaging. The study was performed using a PET/CT scanner. A standard CT bed adapter was attached to the scanner couch. Then, the patient, with the Leksell G frame fixed, was positioned into the scanner with the CT indicator box. PET images were acquired using either [18F]fluorodeoxyglucose or [11C]choline as radioisotopes. After acquisition, CT and PET images were exported in DICOM 3 standard and transferred to a dedicated workstation via data link. Homemade software was implemented for multimodal image fusion. PET images were overwritten to their corresponding CT point values using a threshold algorithm, maintaining the stereotactic CT markers. The use of a CT indicator simplifies the procedure, because there is no need for a radioactive solution filling the indicator box. This method was tested first using a phantom and then in patients. The localization accuracy of the PET images is limited only by the slice thickness.

In patients with the frontal variant of frontotemporal lobar degeneration (fv-FTLD), behavioral abnormalities may vary from apathy with motor slowness (apathetic form) to disinhibition with agitation (disinhibited form). These clinical presentations may be related to specific regional cerebral dysfunction and to deficit in the serotoninergic system. We studied cerebral glucose uptake using 18F-fluorodeoxyglucose and positron emission tomography in 18 patients fulfilling clinical criteria for fv-FTLD and showing, respectively, an apathetic or disinhibited behavioral syndrome. In eight of these patients, we also evaluated the 5-hydroxytryptamine-2A receptor cerebral receptor distribution with [11C]MDL and positron emission tomography. We found a reduction of frontal glucose metabolism in the whole group of fv-FTLD patients. Apathetic syndrome was associated with a prevalent dorsolateral and frontal medial hypometabolism, whereas the disinhibited syndrome demonstrated a selective hypometabolism in interconnected limbic structures (the cingulate cortex, hippocampus/amygdala, and accumbens nucleus). The in vivo measurements of [11C]MDL indicated a significant reduction of 5-hydroxytryptamine-2A receptors in orbitofrontal, frontal medial, and cingulate cortices. These 18F-fluorodeoxyglucose positron emission tomography changes can be considered as specific functional markers of the different behavioral presentations in fv-FTLD. The serotoninergic system dysfunction provides a rationale for therapeutic trials with selective serotonin reuptake inhibitors. Ann Neurol 2005;57:216–225

An in vivo anatomic study of gray matter volume was performed in a group of familial dyslexic individuals, using an optimized method of voxel-based morphometry. Focal abnormalities in gray matter volume were observed bilaterally in the planum temporale, inferior temporal cortex, and cerebellar nuclei, suggesting that the underlying anatomic abnormalities may be responsible for defective written language acquisition in these subjects.

AIM: Increasing ageing of the population and tumor incidence, along with worldwide rationing of the resources for public health systems, spur the use of economic analyses for the choice of strategies and technologies in the assessment and management of cancer patients. Incidence and clinical managing of tumors vary in different countries even if positron emission tomography (PET) with 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) is becoming a routine clinical method for diagnosis, staging, treatment monitoring and follow-up in a variety of tumors. Available data indicate that PET can be considered a superior alternative or complementary tool to other well-established methods. However, in spite of the above and of the rapidly increasing number of PET centers in Europe, USA and Japan, only a few studies have dealt with some of the economic aspects raised by the clinical use of PET because of differences in values of reimbursements and health costs. The main aim of this study is to propose and discuss an economic model of analysis for PET applications in the field of detection and management of pulmonary tumors. METHODS: In this study 2 assessments were performed by decision tree analysis on the economic impact of the availability of PET on decision-making processes for 2 conditions: solitary pulmonary nodules assessment and non-small-cell lung cancer (NSCLC) staging. In order to define a methodology consistent with the system of reimbursement and the prevalent clinical views of the Italian National Health Service, data on costs, death probability, and life expectancy were gathered from the literature and from the Italian system of reimbursement (ROD-DRGs). RESULTS: The results of the cost minimization analysis demonstrate that the use of PET in the diagnostic path for the workup of patients with SPN reduces the overall diagnostic costs, by approximately 50 Euro per patient, by reducing inappropriate invasive diagnostic investigation and their complications. The results of the cost effectiveness analysis demonstrate that the use of PET in the diagnostic path for the staging of patients with NSCLC reduces the overall diagnostic costs by approximately 108 Euro for added year, by reducing inappropriate surgical interventions and their complications. CONCLUSION: Both analyses are based on standard methods used in the literature, so our conclusions can be compared with results and assessments of similar studies in different countries and health care systems. Also in the Italian case, the use of an economic assessment provides relevant information on the efficacy and effectiveness of PET.

Frontotemporal dementia (FTD) is the second commonest form of dementia after Alzheimer's disease, but its clinical and biological features are less well known. To uncover its earliest signs, we studied the main clinical, neuroimaging, and biochemical findings in an asymptomatic carrier from a three generation FTD family, bearing the P301L pathogenic mutation in the tau gene. Except for selective impairment on the Verbal Fluency Test for letters, all cognitive tests were normal. The brain computed tomography scan was normal, but the brain single photon emission computed tomography and statistical parametric mapping (SPECT-SPM) scan revealed bilateral frontal lobe hypoperfusion. Levels of total tau, 181P-tau, and Abeta1-42 in the cerebrospinal fluid were increased compared with control values. We conclude that detection of these distinctive abnormalities should improve early diagnostic accuracy for FTD and help distinguish it from Alzheimer's disease.

Prader-Willi syndrome (PWS) is a multi-system disorder characterized clinically by abnormal mental and physical development. PWS patients have a deletion in an imprinted region on paternal chromosome 15 (15q11-13), maternal disomy for this segment, or rarely, a chromosomal imprinting center deletion that gives rise to suppression of the equivalent paternal genes. Within the affected segment of chromosome 15 are genes encoding the alpha(5), beta(3) and gamma(3) subunits of the gamma-aminobutyric acid type-A (GABA(A)) receptor. Therefore, altered neurobehavioral function could arise in PWS due directly to altered GABA(A) receptor composition and expression, or alternatively, from brain developmental and maturational effects of these or other genes in the imprinted region. The aim of the present study was to assess cerebral GABA(A) receptors in PWS with the use of positron emission tomography of the benzodiazepine binding site employing [11C]flumazenil ([11C]FMZ). A reduction in [11C]FMZ binding was found predominantly in the cingulate, frontal and temporal neocortices and insula in six adult PWS patients compared to nine normal subjects. A possible role for the deleted beta(3) subunit gene in PWS is supported in part by the wide cortical distribution of its mRNA expression and the effects of experimental knockouts on benzodiazepine binding described in prior studies. Altered GABA(A) receptor composition or number in these cortical regions may account for neurobehavioral abnormalities in PWS including mild mental retardation, poor impulse control, and impaired responses to somatic pain.