Nanette Freedman

Resting regional cerebral perfusion in recent posttraumatic stress disorder

BACKGROUNDnBrain imaging research in posttraumatic stress disorder has been largely performed on patients with chronic disease, often heavily medicated, with current or past alcohol and substance abuse. Additionally, virtually only activation brain imaging paradigms have been done in posttraumatic stress disorder, whereas in other mental disorders both resting and activation studies have been performed.nnnMETHODSnTwenty-eight (11 posttraumatic stress disorder) trauma survivors underwent resting state hexamethylpropyleneamineoxime single photon emission computed tomography and magnetic resonance imaging 6 months after trauma. Eleven nontraumatized subjects served as healthy controls.nnnRESULTSnRegional cerebral blood flow in the cerebellum was higher in posttraumatic stress disorder than in both control groups. Regional cerebral blood flow in right precentral, superior temporal, and fusiform gyri in posttraumatic stress disorder was higher than in healthy controls. Cerebellar and extrastriate regional cerebral blood flow were positively correlated with continuous measures of depression and posttraumatic stress disorder. Cortisol level in posttraumatic stress disorder was negatively correlated with medial temporal lobe perfusion. Anterior cingulate perfusion and cortisol level were positively correlated in posttraumatic stress disorder and negatively correlated in trauma survivors without posttraumatic stress disorder.nnnCONCLUSIONSnRecent posttraumatic stress disorder is accompanied by elevated regional cerebral blood flow, particularly in the cerebellum. This warrants attention because the cerebellum is often used as a reference region in regional cerebral blood flow studies. The inverse correlation between plasma cortisol and medial temporal lobe perfusion may herald hippocampal damage.

Potential 18F-labeled biomarkers for epidermal growth factor receptor tyrosine kinase

Abstract As PET candidate tracers for EGFr-TK, five 4-(anilino)quinazoline derivatives, each fluorinated in the aniline moiety, were prepared. Each was tested in vitro for inhibition of EGFr autophosphorylation in A431 cell line. The leading compounds were then radiolabeled with 18 F and cell binding experiments, biodistribution and PET studies in A431 tumor-bearing mice were performed. Metabolic studies were carried out in a mice control group. From our results, we concluded that while in vitro experiments indicates efficacy of 4-(anilino)quinazoline compounds, kinetic factors and rapid blood clearance make them unsuitable as tracers for nuclear medicine imaging of EGFr-TK.

68Ga-DOTA-NOC PET/CT Imaging of Neuroendocrine Tumors: Comparison with 111In-DTPA-Octreotide (OctreoScan®)

PurposeRecent data have indicated that 68Ga-DOTA-NOC positron emission tomography/X-ray computed tomography (PET/CT) may yield improved images in a shorter acquisition protocol than 111In-DTPA-octreotide (OctreoScan®, OCT). Therefore, we performed a prospective comparison of 68Ga-DOTA-NOC and OCT for the detection of neuroendocrine tumors (NETs).MethodsNineteen patients (eight carcinoid, nine pancreatic NETs, and two NE carcinoma of unknown origin) with previous positive OCT scans underwent 68Ga-DOTA-NOC PET/CT and OCT single-photon emission computed tomography imaging for staging or follow-up. Findings were compared by region and verified with conventional imaging.ResultsAll images of both modalities demonstrated focal uptake, often at multiple sites. 68Ga-DOTA-NOC images were clearer than OCT images, facilitating interpretation. Similar foci were identified with both modalities in 41 regions, with additional foci on 68Ga-DOTA-NOC in 21 and on OCT in 15 regions. CT, magnetic resonance imaging, or ultrasound confirmed the concordant findings in 31 of 41 regions and findings seen with 68Ga-DOTA-NOC only in 15 of 21 regions. Findings seen with OCT only were less clear and were only confirmed in 4 of 15 regions. 68Ga-DOTA-NOC had impact on staging in four patients and on management in three patients.ConclusionsAlthough 68Ga-DOTA-NOC and OCT images were similar, in this study, 68Ga-DOTA-NOC demonstrated more true positive tumor foci and was better tolerated by patients. This direct comparison supports replacement of OCT with 68Ga-DOTA-NOC-PET/CT in the evaluation of NETs.

Labeled EGFr-TK irreversible inhibitor (ML03): In vitro and in vivo properties, potential as PET biomarker for cancer and feasibility as anticancer drug

Radiosynthesis of ML03 (N‐{4‐[(4,5‐dichloro‐2‐fluorophenyl)amino]quinazolin‐6‐yl}acrylamide), an irreversible EGFr‐TK inhibitor, was developed. Its in vitro and in vivo properties, its potential as PET biomarker in cancer and the feasibility of this type of compounds to be used as anticancer drug agents were evaluated. The compound was labeled with carbon‐11 at the acryloyl amide group, via automated method with high yield, chemical and radiochemical purities. ELISA carried out with A431 lysate showed high potency of ML03 with an apparent IC50 of 0.037 nM. The irreversible binding nature of ML03 was studied and 97.5% EGFr‐TK autophosphorylation inhibition was observed in intact A431 cells 8 hr post incubation with the inhibitor. Specific binding (67%) of [11C]ML03 was obtained in cells. An A431 tumor‐bearing rat model was developed and the validity of the model was tested. In biodistribution studies carried out with tumor‐bearing rats, moderate uptake was observed in tumor and high uptake in liver, kidney and intestine. In metabolic studies, fast degradation of [11C]ML03 was observed in liver and blood indicating a short half‐life of the compound in the body. PET scan with tumor‐bearing rats confirmed the results obtained in the ex vivo biodistribution studies. Although in vitro experiments may indicate efficacy of ML03, non‐specific binding, ligand delivery and degradation in vivo make ML03 ineffective as PET bioprobe. Derivatives of ML03 with lower metabolic clearance rate and higher bioavailability should be synthesized and their potential as anticancer drugs and PET bioprobes evaluated.

Cerebral glucose utilization and platelet mitochondrial complex I activity in schizophrenia: A FDG-PET study.

Altered cerebral energy metabolism and mitochondrial dysfunction in periphery and in brain are implicated in the pathophysiology of schizophrenia. This study investigated whether cerebral glucose metabolism (rCGM) abnormalities are linked to altered mitochondrial complex I activity in the periphery, in schizophrenia. Sixteen schizophrenic patients, 8 with total positive PANSS score >or=20 (high positive schizophrenics; HPS), and 8 with total positive score <or=12 (low positive schizophrenics; LPS), and 8 healthy subjects, were analyzed for their complex I activity in platelets mitochondria and underwent FDG-PET scans at rest. Complex I activity was significantly increased only in HPS and was positively correlated with positive PANSS scores. Images were spatially normalized to an SPM template, their intensities normalized based on average brain activity. Hypermetabolism was observed in the basal ganglia, thalamus, amygdala, and brainstem of both patient groups compared with controls, and in LPS patients extended to parts of cerebellum, left and right cingulate gyrus, parietal and frontal lobes. rCGM in basal ganglia and thalamus significantly and positively correlated with complex I activity in the HPS. In the LPS, a negative correlation was identified in the cerebellum and brainstem. In the control group, however, no areas demonstrated significant positive or negative correlation. These results suggest that the correlation between peripheral complex I activity and rCGM in regions implicated in schizophrenia, could be a pathological factor that is differentially expressed in subgroups of schizophrenic patients.

SPECT attenuation artifacts in normal and overweight persons : Insights from a retrospective comparison of Rb-82 positron emission tomography and TI-201 SPECT myocardial perfusion imaging

Purpose Myocardial perfusion imaging can be performed using SPECT or positron emission tomography (PET). SPECT has lower specificity than PET, largely as a result of attenuation artifacts; however, it is more widely available. The authors describe a study of the effect of sex and body weight on the incidence of SPECT attenuation artifacts using a retrospective comparison of Tl-201 SPECT and Rb PET. Methods One hundred sixty-one persons (101 men, 60 women; 81 normal weight, 80 overweight) underwent Tl-201 SPECT and Rb PET. The incidence of observed perfusion defects was studied in territories of the three major coronary arteries. SPECT and PET results were also compared with those of angiography in a subset of 75 patients. Results One hundred fourteen defects were reported on Rb PET compared with 176 defects with Tl-201 SPECT. Excess Tl-201 SPECT defects occurred in male and female, normal-weight and overweight persons. The average specificity was 64% for Tl-201 SPECT and 84% for Rb PET, reflecting this difference. Conclusions Attenuation artifacts in Tl-201 SPECT occur frequently and are not confined to easily identifiable subgroups of patients. Therefore, measures to improve specificity of SPECT (e.g., prone or gated imaging) or alternative imaging techniques such as PET have potential advantages for everyone, not simply for obese patients and women with large breasts. In addition, awareness of the prevalence of SPECT attenuation artifacts, in both sexes and all weight categories, may contribute to improved accuracy of interpretation.

18F-Fluorodeoxyglucose-PET/CT Imaging of Lungs in Patients With Cystic Fibrosis

BACKGROUNDnAirway inflammation plays a critical role in the progression of cystic fibrosis (CF) lung disease, and in the destruction of airways and lung parenchyma. Current methods to assess CF lung disease (BAL, spirometry, and high-resolution CT scanning), do not always accurately reflect actual disease states. Fluorodeoxyglucose (FDG)-PET scanning has been used previously to image infection and inflammation. In this study, we assessed the use of (18)F-FDG PET/CT scanning to evaluate and monitor lung inflammation and/or infection in patients with CF.nnnMETHODSnPET/CT scans were performed in 20 patients with CF (age range, 14 to 54 years); 7 of 20 patients underwent repeat PET/CT scans during and after acute exacerbations. The results were compared with clinical information and with images from eight control subjects with no known lung disease.nnnRESULTSnFoci of enhanced activity were observed on FDG-PET scans of patients with CF but not those of control subjects. Higher focal activity (standardized uptake value, > 3.0) was seen during disease exacerbation and infection. Coregistered CT scan images assisted in the localization of PET foci and showed corresponding CT scan findings, with many additional findings on CT scans that were not seen on PET scans. Foci seen on high-intensity PET scans during exacerbations disappeared after antibiotic therapy and the resolution of exacerbation, while corresponding CT scan findings remained unchanged.nnnCONCLUSIONSnPET/CT imaging demonstrated the presence of foci of enhanced uptake that may reflect active focal infectious or inflammatory processes in the lungs. These foci can be cleared with antibiotic therapy. Further studies are needed to validate these results and to determine whether FDG-PET/CT scanning can predict the nature/severity of disease in patients with CF.

Brain SPECT study of common ground between hypothyroidism and depression.

Hypothyroidism and major depressive disorder (MDD) share neuropsychiatric features. Cerebral perfusion deficits are found in both disorders. We compared regional cerebral blood flow (rCBF) in hypothyroidism and MDD to determine if clinical similarities are mediated by common neurocircuitry. Ten hypothyroid and 10 depressed patients underwent 99mTc-HMPAO-SPECT and clinical evaluation before and after response to respective treatments. Ten healthy controls underwent a similar, single, evaluation. Before treatment, rCBF in hypothyroid and depressed patients was lower than in controls, in posterior and anterior aspects of the brain respectively. rCBF in hypothyroidism was lower than in MDD in right posterior cingulate and parieto/occipital regions, and higher in frontal, prefrontal and sub-genual regions. Reduced rCBF in pre- and post-central gyri was found in both groups. Following treatment, rCBF in depressed patients increased and normalized, but remained unchanged in hypothyroidism. Affective symptoms in hypothyroidism may be mediated by neurocircuitry different from that of major depression.

Cerebral blood flow in depressed patients: a methodological comparison of statistical parametric mapping and region of interest analyses.

Functional brain imaging has assumed a leading role in neuropsychiatric research. However, findings reported for mental disorders often vary. Whether this reflects diversity in pathophysiology or heterogeneity of imaging techniques and data-analytic procedures is still unknown. This study compares region of interest (ROI) and statistical parametric mapping (SPM) analyses of a Tc99m-HMPAO single photon emission computed tomography (SPECT) imaging study of 23 depressed and 21 control subjects. Reduced regional cerebral blood flow (rCBF) was demonstrated by both methods in the right parietal and occipital lobes, but additional regions were identified only on ROI analysis (left temporal) and only on SPM analysis (left parietal). To investigate the contribution of SPM spatial normalization to these discrepancies, further ROI analyses were performed, applying the original ROI templates to normalized images, and applying regions identified by SPM to the original images. This study demonstrated considerable overlap in findings of SPM and ROI analyses. Differences between these methods may be mostly related to subjective placement of ROIs in ROI analysis, and standardized warping inherent in normalization in SPM. Given the advantages and drawbacks of each procedure, the choice of methodology should be determined in accordance with the study design, and complementary use of both methods may be considered.

Positron emission tomography in interstitial lung disease.

Background and objectives:u2003 A high rate of glycolysis may reflect the inflammatory activity of interstitial lung disease (ILD). This prospective study investigated whether PET can distinguish IPF, a primarily fibrotic process, from other entities of ILD that have a marked inflammatory component.