Purpose: Positron emission tomography with the radioligand [¹¹C]D-deprenyl has shown an increased signal at the location of pain in patients with ankle sprains, rheumatoid arthritis and chronic whiplash injury, but the mechanism of this tracer uptake and its exact binding site in inflammation or tissue injury is still unclear. The aim of this study was to further evaluate [¹¹C]D-deprenyl´s usefulness as a marker of acute inflammation.

Methods: An animal PET/CT study was performed three days after the induction of a rat model of inflammatory or surgical pain. Fourteen adult male Sprague-Dawley rats and three tracers [¹¹C]D-deprenyl, [¹¹C]L-dideuterumdeprenyl and [¹⁸F]fluorodeoxyglucose were used.

Results: No [¹¹C]D-deprenyl accumulation was seen in a rat model of musculoskeletal pain. In the rat model of inflammatory pain all three ligands were shown to visualize the inflamed ankle joint with much lower uptake in the control ankle joint. The uptake was largest with [¹¹C]D-deprenyl and [¹¹C]L- dideuteriumdeprenyl, where approximately 1 % of the injected dose could be found in the affected ankle joint during the first minutes, whereas the uptake of [¹⁸F]FDG was approximately 0.5 % of the injected dose. However, the ratio of uptake of the injected ankle joint versus the control ankle joint was much higher for [¹⁸F]FDG (around 10 fold increase) than for the two deprenyl enantiomers (2 – 3 fold increase). The uptake pattern of [¹¹C]D-deprenyl and [¹¹C]L-dideuteriumdeprenyl did not show signs of specific binding or irreversible trapping.

Conclusions: Contrary to our expectations, of the three tracers only [¹⁸F]FDG may be used as markers of peripheral inflammation in a rat model of inflammatory pain. However, as a high site-specificity is required, [¹¹C]D-deprenyl and [¹¹C]L-dideyteriumdeprenyl deserve further exploration regarding sensitivity, specificity and uptake mechanisms in human pain syndromes.

The understanding of etiological mechanisms of whiplash associated disorder is still inadequate. Objective visualization and quantification of peripheral musculoskeletal injury and possible painful inflammation in whiplash associated disorder would facilitate diagnosis, strengthen patients’ subjective pain reports and aid clinical decisions eventually leading to better treatments. In the current study, we further evaluated the potential to use [¹¹C]D-deprenyl PET/CT to visualize inflammation after whiplash injury. Sixteen patients with whiplash injury grade II were recruited at the emergency department and underwent [¹¹C]D-deprenyl PET/CT in the acute phase and at 6 months after injury. Subjective pain levels, self rated neck disability and active cervical range of motion were recorded at each imaging session. Results showed that the molecular aspects of inflammation and possible tissue injuries after acute whiplash injury could be visualized, objectively quantified and followed over time with [¹¹C]-D-deprenyl PET/CT. An altered [¹¹C]D-deprenyl uptake in the cervical bone structures and facet joints was associated with subjective pain levels and self rated disability during both imaging occasions. These findings may contribute to a better understanding of affected peripheral structures in whiplash injury and strengthens the idea that PET/CT detectable organic lesions in peripheral tissue may be relevant for the development of persistent pain and disability in whiplash injury.

Perspective: This article presents a novel way of objectively visualizing possible structural damage and inflammation that cause pain and disability in whiplash injury. This PET method can bring an advance in pain research and eventually would facilitate the clinical management of patients in pain.

Affibody molecules (6-7 kDa) are a new class of small robust three-helical scaffold proteins. Radiolabeled subnanomolar anti-HER2 affibody Z(HER2:342) was developed for imaging of HER2 expression in tumors, and a clinical study has demonstrated that the In-111- and Ga-68-labeled affibody molecules can efficiently detect HER2 expressing metastases in breast cancer patients. However, a significant renal accumulation of radioactivity after systemic injection of a radiolabeled anti-HER2 affibody conjugate is observed. The aim of this study was to investigate the mechanism of renal reabsorption of anti-HER2 affibody at the molecular level. Renal accumulation of radiolabeled anti-HER2 affibody molecules was studied in a murine model and in vitro using opossum-derived proximal tubule (OK) cells. It was found that kidney reabsorption of affibody molecule was not driven by megalin/cubilin. Amino acids in the target-binding side of affibody molecule were involved in binding to OK cells. On OK cells, two types of receptors for anti-HER2 affibody molecule were found: K-D1 = 0.8 nM, B-max1 = 71,500 and K-D2 = 9.2 nM, B-max2 = 367,000. The results of the present study indicate that affibody molecule and other scaffold-based targeting proteins with a relatively low kidney uptake can be selected using in vitro studies with tubular kidney cells.

Affibody molecules are small (7 kDa) nonimmunoglobulin scaffold proteins with favorable tumor-targeting properties. Studies concerning the influence of chelators on biodistribution of ^99mTc-labeled Affibody molecules demonstrated that the variant with a C-terminal glycyl-glycyl-glycyl-cysteine peptide–based chelator (designated Z_HER2:V2) has the best biodistribution profile in vivo and the lowest renal retention of radioactivity. The aim of this study was to evaluate ¹⁸⁸Re-Z_HER2:V2 as a potential candidate for radionuclide therapy of human epidermal growth factor receptor type 2 (HER2)–expressing tumors.

Methods:

Z_HER2:V2 was labeled with ¹⁸⁸Re using a gluconate-containing kit. Targeting of HER2-overexpressing SKOV-3 ovarian carcinoma xenografts in nude mice was studied for a dosimetry assessment.

Results:

Binding of ¹⁸⁸Re-Z_HER2:V2 to living SKOV-3 cells was demonstrated to be specific, with an affinity of 6.4 ± 0.4 pM. The biodistribution study showed a rapid blood clearance (1.4 ± 0.1 percentage injected activity per gram [%ID/g] at 1 h after injection). The tumor uptake was 14 ± 2, 12 ± 2, 5 ± 2, and 1.8 ± 0.5 %IA/g at 1, 4, 24, and 48 h after injection, respectively. The in vivo targeting of HER2-expressing xenografts was specific. Already at 4 h after injection, tumor uptake exceeded kidney uptake (2.1 ± 0.2 %IA/g). Scintillation-camera imaging showed that tumor xenografts were the only sites with prominent accumulation of radioactivity at 4 h after injection. Based on the biokinetics, a dosimetry evaluation for humans suggests that ¹⁸⁸Re-Z_HER2:V2 would provide an absorbed dose to tumor of 79 Gy without exceeding absorbed doses of 23 Gy to kidneys and 2 Gy to bone marrow. This indicates that future human radiotherapy studies may be feasible.

Conclusion:

¹⁸⁸Re-Z_HER2:V2 can deliver high absorbed doses to tumors without exceeding kidney and bone marrow toxicity limits.

Combining MRI morphological data with functional PET data offers significant advantages in research as well as in many clinical situations. Automatic methods are needed, however, to coregister the data from the two modalities.

METHODS:

Simulated PET images were created by simple and automatic segmentation of MR images followed by the assignment of different uptake values to various tissue types. The simulated PET images were registered to actual PET images using a pixel-by-pixel, PET-PET registration method. The transformation matrix was then applied to the MR images. The method was used to register MRI data to PET transmission scans and emission scans obtained with FDG, nomifensine and raclopride. Validation was performed by comparing the results to those obtained by matching internal points manually defined in both volumes.

RESULTS:

Emission and transmission PET images were successfully registered to MR data. Comparison to the manual method indicated a registration accuracy on the order of 1-2 mm in each direction. No difference in accuracy between the different tracers was found. The error sensitivity for the method's assumptions seemed to be sufficiently low to allow complete automation of the method.

CONCLUSION:

We present a rapid, robust and fully automated method to register PET and MR brain images with sufficient accuracy for most clinical applications.

Expression of human epidermal growth factor receptor type 3 (HER3) in malignant tumors has been associated with resistance to a variety of anticancer therapies. Several anti-HER3 monoclonal antibodies are currently under pre-clinical and clinical development aiming to overcome HER3-mediated resistance. Radionuclide molecular imaging of HER3 expression may improve treatment by allowing the selection of suitable patients for HER3-targeted therapy. Affibody molecules are a class of small (7 kDa) high-affinity targeting proteins with appreciable potential as molecular imaging probes. In a recent study, we selected affibody molecules with affinity to HER3 at a low picomolar range. The aim of the present study was to develop an anti-HER3 affibody molecule suitable for labeling with radiometals. The HEHEHE-Z08698-NOTA and HEHEHE-Z08699-NOTA HER3-specific affibody molecules were labeled with indium-111 (In-111) and assessed in vitro and in vivo for imaging properties using single photon emission computed tomography (SPECT). Labeling of HEHEHE-Z08698-NOTA and HEHEHE-Z08699-NOTA with In-111 provided stable conjugates. In vitro cell tests demonstrated specific binding of the two conjugates to HER3-expressing BT-474 breast carcinoma cells. In mice bearing BT-474 xenografts, the tumor uptake of the two conjugates was receptor-specific. Direct in vivo comparison of In-111-HEHEHE-Z08698-NOTA and In-111-HEHEHE-Z08699-NOTA demonstrated that the two conjugates provided equal radioactivity uptake in tumors, although the tumor-to-blood ratio was improved for In-111-HEHEHE-Z08698-NOTA [12 +/- 3 vs. 8 +/- 1,4 h post injection (p.i)] due to more efficient blood clearance. In-111-HEHEHE-Z08698-NOTA is a promising candidate for imaging of HER3-expression in malignant tumors using SPECT. Results of the present study indicate that this conjugate could be used for patient stratification for anti-HER3 therapy.

Cardiac amyloidosis is a differential diagnosis in heart failure and is associated with high mortality. There is currently no noninvasive imaging test available for specific diagnosis. N-[methyl-¹¹C]2-(4′-methylamino-phenyl)-6-hydroxybenzothiazole (¹¹C-PIB) PET is used in the evaluation of brain amyloidosis. We evaluated the potential use of ¹¹C-PIB PET in systemic amyloidosis affecting the heart.

Methods:

Patients (n = 10) diagnosed with systemic amyloidosis—including heart involvement of either monoclonal immunoglobulin light-chain (AL) or transthyretin (ATTR) type—and healthy volunteers (n = 5) were investigated with PET/CT using ¹¹C-PIB to study cardiac amyloid deposits and with ¹¹C-acetate to measure myocardial blood flow to study the impact of global and regional perfusion on PIB retention.

Results:

Myocardial ¹¹C-PIB uptake was visually evident in all patients 15–25 min after injection and was not seen in any volunteer. A significant difference in ¹¹C-PIB retention in the heart between patients and healthy controls was found. The data indicate that myocardial amyloid deposits in patients diagnosed with systemic amyloidosis could be visualized with ¹¹C-PIB. No correlation between ¹¹C-PIB retention index and myocardial blood flow as measured with ¹¹C-acetate was found on the global level, whereas a positive correlation on the segmental level was seen in a single patient.

Conclusion:

¹¹C-PIB and PET could be a method to study systemic amyloidosis of type AL and ATTR affecting the heart and should be investigated further both as a diagnostic tool and as a noninvasive method for treatment follow-up.

l-2,4-Diamino[4-¹¹C]butyric acid (DAB) was synthesized by an enzyme catalysed carrier added (0.1 μmol KCN) reaction of hydrogen [¹¹C]cyanide with O-acetyl-l-serine followed by reduction. l-[¹¹C]DAB was obtained with a radiochemical purity higher than 96% and with a decay corrected radiochemical yield of 30–40% within a 32 min reaction time. The enantiomeric excess was 98%. The uptake of l-[¹¹C]DAB was investigated in multicellular aggregates of six different cell lines and animal tumour models. l-[¹¹C]DAB is potentially useful for the assessment of pharmacokinetics of l-DAB in vivo for part of its evaluation as an antitumoural agent, although its use for diagnostic purposes seems limited.

Positron emission tomography (PET) visualization of brain components in vivo is a rapidly growing field. Molecular imaging with PET is also increasingly used in drug development, especially for the determination of drug receptor interaction for CNS-active drugs. This gives the opportunity to relate clinical efficacy to per cent receptor occupancy of a drug on a certain targeted receptor and to relate drug pharmacokinetics in plasma to interaction with target protein. In the present review we will focus on the study of transporters, such as the monoamine transporters, the P-glycoprotein (Pgp) transporter, the vesicular monoamine transporter type 2, and the glucose transporter using PET radioligands. Neurotransmitter transporters are presynaptically located and in vivo imaging using PET can therefore be used for the determination of the density of afferent neurons. Several promising PET ligands for the noradrenaline transporter (NET) have been labeled and evaluated in vivo including in man, but a really useful PET ligand for NET still remains to be identified. The most promising tracer to date is (S,S)-[¹⁸F]FMeNER-D₂. The in vivo visualization of the dopamine transporter (DAT) may give clues in the evaluation of conditions related to dopamine, such as Parkinson's disease and drug abuse. The first PET radioligands based on cocaine were not selective, but more recently several selective tracers such as [¹¹C]PE2I have been characterized and shown to be suitable as PET radioligands. Although there are a large number of serotonin transporter inhibitors used today as SSRIs, it was not until very recently, when [¹¹C]McN5652 was synthesized, that this transporter was studied using PET. New candidates as PET radioligands for the SERT have subsequently been developed and [¹¹C]DASB and [¹¹C]MADAM and their analogues are today the most promising ligands. The existing radioligands for Pgp transporters seem to be suitable tools for the study of both peripheral and central drug–Pgp interactions, although [¹¹C]verapamil and [¹⁸F]fluoropaclitaxel are probably restricted to use in studies of the blood–brain barrier. The vesicular monoamine transporter 2 (VMAT2) is another interesting target for diagnostic imaging and [¹¹C]DTBZ is a promising tracer. The noninvasive imaging of transporter density as a function of disease progression or availability following interaction with blocking drugs is highlighted, including the impact on both development of new therapies and the process of developing new drugs. Although CNS-related work focusing on psychiatric disorders is the main focus of this review, other applications of PET ligands, such as diagnosis of cancer, diabetes research, and drug interactions with efflux systems, are also discussed. The use of PET especially in terms of tracer development is briefly described. Finally, it can be concluded that there is an urgent need for new, selective radioligands for the study of the transporter systems in the human brain using PET.

Hemophagocytic lymphohistiocytosis (HLH) is an aggressive inflammatory syndrome that results from inappropriate activation of the immune system. HLH has a high mortality if not treated. We describe a case of a fulminant HLH, associated with a reactivation of an EBV infection. The patient responded well to steroid treatment.

Tesofensine (TE) is a novel triple monoannine re-uptake inhibitor inducing a potent inhibition of the re-uptake process in the synaptic cleft of the neurotransmitters dopamine, norepinephrine, and serotonin. In recent preclinical and clinical evaluations TE showed a robust anti-obesity effect, but the specific mechanism of this triple monoamine re-uptake inhibitor still needs to be further elucidated. This positron emission tomography (PET) study, using [C-11]beta CIT-FE, aimed to assess the degree of the dopamine transporter (DAT) occupancy, at constant TE plasma levels, following different oral, multiple doses of TE during totally 8-12 days. In addition, the relationships between DAT occupancy and TE plasma concentrations, or doses, were investigated to enable assessment of DAT occupancies in subsequent clinical trials. The results demonstrated that TE induced a dose-dependent blockade of DAT following multiple doses of 0.125-1 mg TE at anticipated steady-state conditions. The mean striatal DAT occupancy varied dose-dependently between 18% and 77%. A signnoid E-max model well described the relationship between striatal DAT occupancy and TE plasma concentrations or doses. It was estimated that the maximum achievable DAT occupancy was about 80% and that half of this effect was accomplished by approximately 0.25 mg TE and a plasma drug concentration of 4 ng/ml. The results indicated an important mechanism of action of TE on DAT. Further, these results suggest that the previously reported dose-dependent weight loss, in TE treated subjects, was in part mediated by an up-regulation of dopaminergic pathways due to enhanced amounts of synaptic dopamine after blockade of DAT.

BL-1020 is a potentially novel antipsychotic, which comprises the typical antipsychotic perphenazine linked by an ester bound to gamma-aminobutyric acid (GABA), intending a simultaneous dopamine-2 (D(2)) receptor blockade and GABA facilitation in the brain. This positron emission tomography (PET) study, using [(11)C]raclopride, assessed the extent and duration of D(2) receptor occupancy (D(2) RO) and safety for single doses of BL-1020 in healthy male subjects. Overall, this study did not raise any safety concern. Single doses of 16-32 mg BL-1020 caused a dose dependent striatal D(2) RO. The 32 mg dose of BL-1020 resulted in an average D(2) RO of 44% at 4-6 h post dosing (pd), which declined to 33% at 24 h pd. Equimolar doses of BL-1020 and perphenazine resulted in similar D(2) RO at 24 h pd. Pharmacokinetic-pharmacodynamic analysis predicted that oral once daily administration of 32 mg BL-1020 would result in D(2) ROs ranging from 52 to 66% at a steady state.

In idiopathic Parkinson disease and atypical parkinsonian disorders, central dopaminergic and overall brain functional activity are altered to different degrees, causing difficulties in achieving an unambiguous clinical diagnosis. A dual examination using I-123-FP-CIT (I-123-N-omega-fluoropropyl- 2 beta-carbomethoxy-3 beta-(4-iodophenyl) nortropane, or I-123-ioflupane) SPECT and F-18-FDG PET provides complementary information on dopamine transporter (DAT) availability and overall brain functional activity, respectively. Parametric images based on a single, dynamic C-11-PE2I (N-(3-iodoprop-2E-enyl)-2 beta-carbomethoxy-3 beta-(4-methyl-phenyl) nortropane) scan potentially supply both DAT availability (nondisplaceable binding potential [BPND]) and relative cerebral blood flow (relative delivery [R-1]) at voxel level. This study aimed to evaluate the validity of C-11-PE2I PET against the dual-modality approach using I-123-FP-CIT SPECT and F-18-FDG PET.

Methods: Sixteen patients with parkinsonian disorders had a dual examination with F-18-FDG PET and I-123-FP-CIT SPECT following clinical routines and additionally an experimental C-11-PE2I PET scan. Parametric BPND and R-1 images were generated using receptor parametric mapping with the cerebellum as a reference. T1-weighted MR imaging was used for automated definition of volumes of interest (VOI). The DAT VOIs included the basal ganglia, whereas the overall brain functional activity was examined using VOIs across the brain. BPND and R-1 values were compared with normalized I-123-FP-CIT and F-18-FDG uptake values, respectively, using Pearson correlations and regression analyses. In addition, 2 masked interpreters evaluated the images visually, in both the routine and the experimental datasets, for comparison of patient diagnoses.

Results: Parametric C-11-PE2I BPND and R-1 images showed high consistency with I-123-FP-CIT SPECT and F-18-FDG PET images. Correlations between C-11-PE2I BPND and I-123-FP-CIT uptake ratios were 0.97 and 0.76 in the putamen and caudate nucleus, respectively. Regional C-11-PE2I R-1 values were moderately to highly correlated with normalized F-18-FDG values (range, 0.61-0.94). Visual assessment of DAT availability showed a high consistency between C-11-PE2I BPND and I-123-FP-CIT images, whereas the consistency was somewhat lower for appraisal of overall brain functional activity using I-123-FP-CIT and F-18-FDG images. Substantial differences were found between clinical diagnosis and both neuro-imaging diagnoses.

Conclusion: A single, dynamic C-11-PE2I PET investigation is a powerful alternative to a dual examination with I-123-FP-CIT SPECT and F-18-FDG PET for differential diagnosis of parkinsonian disorders. A large-scale patient study is, however, needed to further investigate distinct pathologic patterns in overall brain functional activity for various parkinsonian disorders.

PURPOSE: To evaluate whether, in patients with non-small cell lung carcinoma (NSCLC), tumor uptake of [(11)C]erlotinib can be quantified and imaged using positron emission tomography and to assess whether the level of tracer uptake corresponds with the presence of activating tumor EGF receptor (EGFR) mutations.EXPERIMENTAL DESIGN: Ten patients with NSCLCs, five with an EGFR exon 19 deletion, and five without were scanned twice (test retest) on the same day with an interval of at least 4 hours. Each scanning procedure included a low-dose computed tomographic scan, a 10-minute dynamic [(15)O]H(2)O scan, and a 1-hour dynamic [(11)C]erlotinib scan. Data were analyzed using full tracer kinetic modeling. EGFR expression was evaluated using immunohistochemistry.RESULTS: The quantitative measure of [(11)C]erlotinib uptake, that is, volume of distribution (V(T)), was significantly higher in tumors with activating mutations, that is, all with exon 19 deletions (median V(T), 1.76; range, 1.25-2.93), than in those without activating mutations (median V(T), 1.06; range, 0.67-1.22) for both test and retest data (P = 0.014 and P = 0.009, respectively). Good reproducibility of [(11)C]erlotinib V(T) was seen (intraclass correlation coefficient = 0.88). Intergroup differences in [(11)C]erlotinib uptake were not correlated with EGFR expression levels, nor tumor blood flow.CONCLUSION: [(11)C]erlotinib V(T) was significantly higher in NSCLCs tumors with EGFR exon 19 deletions.

Essential for detection of relevant external stimuli and for fear processing, the amygdala is under modulatory influence of dopamine (DA). The DA transporter (DAT) is of fundamental importance for the regulation of DA transmission by mediating reuptake inactivation of extracellular DA. This study examined if a common functional variable number tandem repeat polymorphism in the 3' untranslated region of the DAT gene (SLC6A3) influences amygdala function during the processing of aversive emotional stimuli. Amygdala reactivity was examined by comparing regional cerebral blood flow, measured with positron emission tomography and [O-15] water, during exposure to angry and neutral faces, respectively, in a Swedish sample comprising 32 patients with social anxiety disorder and 17 healthy volunteers. In a separate US sample, comprising 85 healthy volunteers studied with blood oxygen level-dependent functional magnetic resonance imaging, amygdala reactivity was assessed by comparing the activity during exposure to threatening faces and neutral geometric shapes, respectively. In both the Swedish and the US sample, 9-repeat carriers displayed higher amygdala reactivity than 10-repeat homozygotes. The results suggest that this polymorphism contributes to individual variability in amygdala reactivity.

The purpose of the study was to evaluate PET with the tracer 11C-metomidate as a method to identify adrenal cortical lesions.

METHODS:

PET with 11C-metomidate was performed in 15 patients with unilateral adrenal mass confirmed by CT. All patients subsequently underwent surgery, except 2 who underwent biopsy only. The lesions were histopathologically examined and diagnosed as adrenal cortical adenoma (n = 6; 3 nonfunctioning), adrenocortical carcinoma (n = 2), and nodular hyperplasia (n = 1). The remaining were noncortical lesions, including 1 pheochromocytoma, 1 myelolipoma, 2 adrenal cysts, and 2 metastases.

RESULTS:

All cortical lesions were easily identified because of exceedingly high uptake of 11C-metomidate, whereas the noncortical lesions showed very low uptake. High uptake was also seen in normal adrenal glands and in the stomach. The uptake was intermediate in the liver and low in other abdominal organs. Images obtained immediately after tracer injection displayed high uptake in the renal cortex and spleen. The tracer uptake in the cortical lesions increased throughout the examination. For quantitative evaluation of tracer binding in individual lesions, a model with the splenic radioactivity concentration assigned to represent nonspecific uptake was applied. Values derived with this method, however, did show the same specificity as the simpler standardized uptake value concept, with similar difference observed for cortical versus noncortical lesions.

CONCLUSION:

PET with 11C-metomidate has the potential to be an attractive method for the characterization of adrenal masses with the ability to discriminate lesions of adrenal cortical origin from noncortical lesions.

Purpose:

The purpose of the study was to evaluate the potential role of PET with the adrenocortical-specific tracer ¹¹C-metomidate in the characterization of incidentally found adrenal cortical lesions and in adrenocortical carcinomas.

Methods:

PET with ¹¹C-metomidate was performed in 15 patients with unilateral adrenal mass confirmed by CT (incidentalomas) and in 9 additional patients with adrenocortical cancer. All incidentalomas subsequently underwent surgery, except 2 subjected to biopsy only. These lesions were histopathologically examined and diagnosed as adrenal cortical adenoma (n = 6; 3 nonfunctioning), adrenocortical carcinoma (n = 2) and nodular hyperplasia (n = 1). The remaining were non-cortical lesions including 1 pheochromocytoma, 1 myelolipoma, 2 adrenal cysts, and 2 metastases.

Results:

All lesions, except 1, with an adrenocortical origin were easily identified due to exceedingly high uptake of ¹¹C-metomidate, whereas the non-cortical lesions showed very low uptake. The 1 false negative was a cancer that at surgery was found to be extensively necrotic. High uptake was also seen in normal adrenal glands. The tracer uptake kinetics indicated trapping of the tracer in the cortical lesions. For quantitative evaluation of tracer binding in individual lesions, the simple SUV concept was found to be equally accurate as more elaborate kinetic analyses.

Conclusion:

The patients presented and altogether over 40 PET investigations have demonstrated ¹¹C-metomidate to be an attractive tracer for the characterization of adrenal masses with the ability to discriminate lesions of adrenal cortical origin from non-cortical lesions. Additionally the method allows the assessment of metastases from adrenocortical cancers, and the very high contrast has allowed partial whole-body examinations.

Perfusion and diffusion magnetic resonance imaging (pMRI, dMRI) are valuable diagnostic tools for assessing brain tumors in the clinical setting. The aim of this study was to determine the correlation of pMRI and dMRI with (11)C-methionine positron emission tomography (MET PET) in suspected low-grade gliomas (LGG) prior to surgery. Twenty-four adults with suspected LGG were enrolled in an observational study and examined by MET PET, pMRI and dMRI. Histological tumor diagnosis was confirmed in 23/24 patients (18 gliomas grade II, 5 gliomas grade III). The maximum relative cerebral blood volume (rCBVmax) and the minimum mean diffusivity (MDmin) were measured in tumor areas with highest MET uptake (hotspot) on PET by using automated co-registration of MRI and PET scans. A clearly defined hotspot on PET was present in all 23 tumors. Regions with rCBVmax corresponded with hotspot regions in all tumors, regions with MDmin corresponded with hotspot regions in 20/23 tumors. The correlation between rCBVmax (r = 0.19, P = 0.38) and MDmin (r = -0.41, P = 0.053) with MET uptake in the hotspot was not statistically significant. Taken into account the difficulties of measuring perfusion abnormalities in non-enhancing gliomas, this study demonstrates that co-registered MET PET and pMRI facilitates the identification of regions with rCBVmax. Furthermore, the lack of a clear positive correlation between tumor metabolism in terms of MET uptake and tumor vascularity measured as rCBVmax suggests that combined pMRI/PET provides complementary baseline imaging data in these tumors.

Parenteral iron-polysaccharide complexes are increasingly applied. The pharmacokinetics of iron sucrose have been assessed by our group using positron emission tomography (PET). A single intravenous injection of 100 mg iron as iron (III) hydroxide-polymaltose complex, labelled with a tracer in the form of ⁵²Fe/⁵⁹Fe, was similarly assessed in six patients using PET for about 8 h. Red cell utilization was followed for 4 weeks. Iron polymaltose was similarly distributed to the liver, spleen and bone marrow. However, a larger proportion of this complex was rapidly distributed to the bone marrow. The shorter equilibration phase for the liver, about 25 min, indicates the minimal role of the liver for direct distribution. Splenic uptake also reflected the reticuloendothelial handling of this complex. Red cell utilization ranged from 61% to 99%. Despite the relatively higher uptake by the bone marrow, there was no saturation of marrow transport systems at this dose level. In conclusion, high red cell utilization of iron polymaltose occurred in anaemic patients. The major portion of the injected dose was rapidly distributed to the bone marrow. In addition, the reticuloendothelial uptake of this complex may reflect the safety of polysaccharide complexes. Non-saturation of transport systems to the bone marrow indicated the presence of a large interstitial transport pool, which might possibly be transferrin.

Several peptides comprising Arg-Gly-Asp (RGD) domain and macrocyclic chelator were labeled with Ga-68 for the imaging of angiogenesis. The analogues varied in peptide constitution, linker and chelator type. The labeling efficiency did not vary with the peptide constitution and linker type, but depended on the chelator type. Four of the compounds containing 2,2', 2 '', 2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl) tetraacetic acid (DOTA) chelator were labeled at 90 +/- 5 degrees C using conventional or microwave heating reaching 90% of Ga-68 incorporation after 5 and 2 min respectively, when the concentration of the precursor was 2.5 mu M. The compound having 2,2', 2 ''-(1,4,7-triazonane1,4,7-triyl)triacetic acid (NOTA) as the chelator could be labeled at room temperature within 5 min using 2.5 mu M peptide precursor. Two of the compounds contained a poly (ethylene glycol) (PEG) linker to the chelator. The biodistribution of the analogues was studied in male rats.

Ventilation distribution can be assessed by SPECT with Technegas. This study was undertaken in piglets with different degrees of ventilation inhomogeneity to compare PET using Ga-68-labeled pseudogas or "Gallgas" with Technegas. Methods: Twelve piglets were studied in 3 groups: control, lobar obstruction, and diffuse airway obstruction. Two more piglets were assessed for lung volume (functional residual capacity). Results: In controls, SPECT and PET images showed an even distribution of radioactivity. With lobar obstruction, the absence of ventilation of the obstructed lobe was visible with both techniques. In diffuse airway obstruction, SPECT images showed an even distribution of radioactivity, and PET images showed more varied radioactivity over the lung. Conclusion: PET provides detailed ventilation distribution images and a better appreciation of ventilation heterogeneity. Gallgas with PET is a promising new diagnostic tool for the assessment of ventilation distribution.

Objectives:The aim of this study was to investigate predictors of progressive cognitive deterioration in patients with suspected non-Alzheimer disease pathology (SNAP) and mild cognitive impairment (MCI).Methods:We measured markers of amyloid pathology (CSF -amyloid 42) and neurodegeneration (hippocampal volume on MRI and cortical metabolism on [F-18]-fluorodeoxyglucose-PET) in 201 patients with MCI clinically followed for up to 6 years to detect progressive cognitive deterioration. We categorized patients with MCI as A+/A- and N+/N- based on presence/absence of amyloid pathology and neurodegeneration. SNAPs were A-N+ cases.Results:The proportion of progressors was 11% (8/41), 34% (14/41), 56% (19/34), and 71% (60/85) in A-N-, A+N-, SNAP, and A+N+, respectively; the proportion of APOE epsilon 4 carriers was 29%, 70%, 31%, and 71%, respectively, with the SNAP group featuring a significantly different proportion than both A+N- and A+N+ groups (p 0.005). Hypometabolism in SNAP patients was comparable to A+N+ patients (p = 0.154), while hippocampal atrophy was more severe in SNAP patients (p = 0.002). Compared with A-N-, SNAP and A+N+ patients had significant risk of progressive cognitive deterioration (hazard ratio = 2.7 and 3.8, p = 0.016 and p < 0.001), while A+N- patients did not (hazard ratio = 1.13, p = 0.771). In A+N- and A+N+ groups, none of the biomarkers predicted time to progression. In the SNAP group, lower time to progression was correlated with greater hypometabolism (r = 0.42, p = 0.073).Conclusions:Our findings support the notion that patients with SNAP MCI feature a specific risk progression profile.

The biomarker-based new diagnostic criteria have been proposed for Alzheimer's disease (AD) spectrum. However, any biomarker alone has not been known to have satisfactory AD predictability. We explored the best combination model with baseline demography, neuropsychology, F-18-fluorodeoxyglucose positron emission tomography (FDG-PET), cerebrospinal fluid (CSF) biomarkers, and apolipoprotein E (APOE) genotype evaluation to predict progression to AD in mild cognitive impairment (MCI) patients. Alongitudinal clinical follow-up (mean, 44 months; range, 1.6-161.7 months) of MCI patients was done. Among 83 MCI patients, 26 progressed to AD (MCI-AD) and 51 did not deteriorate (MCI-Stable). We applied that univariate and multivariate logistic regression analyses, and multistep model selection for AD predictors including biomarkers. In univariate logistic analysis, we selected age, Rey Auditory Verbal Retention Test, parietal glucose metabolic rate, CSF total tau, and presence or not of at least one APOE epsilon 4 allele as predictors. Through multivariate stepwise logistic analysis and model selection, we found the combination of parietal glucose metabolic rate and total tau representing the best model for AD prediction. In conclusion, our findings highlight that the combination of regional glucose metabolic assessment by PET and CSF biomarkers evaluation can significantly improve AD predictive diagnostic accuracy of each respective method.

Hybrid imaging using PET in conjunction with CT-based coronary angiography (PET/CTCA) enables near-simultaneous quantification of myocardial blood flow (MBF) and anatomical evaluation of coronary arteries. CTCA is an excellent imaging modality to rule out obstructive coronary artery disease (CAD), but functional assessment is warranted in the presence of a CTCA-observed stenosis because the specificity of CTCA is relatively low. Quantitative H 2 15O PET/CTCA may yield complementary information and enhance diagnostic accuracy. The purpose of this study was to evaluate the diagnostic accuracy of quantitative H2 15O PET/CTCA in a clinical cohort of patients with suspected CAD who underwent both cardiac H 2 15O PET/CTCA and invasive coronary angiography (ICA). In addition, this study aimed to evaluate and compare the accuracy of hyperemic MBF versus coronary flow reserve (CFR). Methods: Patients (n = 120; mean age ± SD, 61 ± 10 y; 77 men and 43 women) with a predominantly intermediate pretest likelihood for CAD underwent both quantitative H 2 15O PET/CTCA and ICA. A ≥50% stenosis at ICA or a fractional flow reserve ≤ 0.80 was considered significant. Results: Obstructive CAD was diagnosed in 49 of 120 patients (41%). The diagnostic accuracy of hyperemic MBF was significantly higher than CFR (80% vs. 68%, respectively, P = 0.02), with optimal cutoff values of 1.86 mL/min/g and 2.30, respectively. On a per-patient basis, the sensitivity, specificity, negative predictive value, and positive predictive value of CTCA were 100%, 34%, 100%, and 51%, respectively, as compared with 76%, 83%, 83%, and 76%, respectively, for quantitative hyperemic MBF PET. Quantitative H2 15O PET/CTCA reduced the number of false-positive CTCA studies from 47 to 6, although 12 of 49 true-positive CTCAs were incorrectly reclassified as false-negative hybrid scans on the basis of (presumably) sufficient hyperemic MBF. Compared with CTCA (61%) or H2 15O PET (80%) alone (both P &lt; 0.05), the hybrid approach significantly improved diagnostic accuracy (85%). Conclusion: The diagnostic accuracy of quantitative H 2 15O PET/CTCA is superior to either H2 15O PET or CTCA alone for the detection of clinically significant CAD. Hyperemic MBF was more accurate than CFR, implying that a single measurement of MBF in diagnostic protocols may suffice.

Background Myocardial ischaemia occurs principally in the subendocardial layer, whereas conventional myocardial perfusion imaging provides no information on the transmural myocardial blood flow (MBF) distribution. Subendocardial perfusion measurements and quantification of the transmural perfusion gradient (TPG) could be more sensitive and specific for the detection of coronary artery disease (CAD). The current study aimed to determine the impact of lesion severity as assessed by the fractional flow reserve (FFR) on subendocardial perfusion and the TPG using [O-15]H2O positron emission tomography (PET) imaging in patients evaluated for CAD. Methods and results Sixty-six patients with anginal chest pain were prospectively enrolled and underwent [O-15] H2O myocardial perfusion PET imaging. Subsequently, invasive coronary angiography was performed and FFR obtained in all coronary arteries irrespective of the PET imaging results. Thirty (45%) patients were diagnosed with significant CAD(i.e. FFR <= 0.80), whereas on a per vessel analysis (n = 198), 53 (27%) displayed a positive FFR. Transmural hyperaemic MBF decreased significantly from 3.09 +/- 1.16 to 1.67 +/- 0.57 mL min(-1) g(-1) (P < 0.001) in non-ischaemic and ischaemic myocardium, respectively. The TPG decreased during hyperaemia when compared with baseline (1.20 +/- 0.14 vs. 0.94 +/- 0.17, P < 0.001), and was lower in arteries with a positive FFR (0.97 +/- 0.16 vs. 0.88 +/- 0.18, P < 0.01). ATPG threshold of 0.94 yielded an accuracy to detect CAD of 59%, which was inferior to transmural MBF with an optimal cutoff of 2.20 mL min(-1) g(-1) and an accuracy of 85% (P < 0.001). Diagnostic accuracy of subendocardial perfusion measurements was comparable with transmural MBF (83 vs. 85%, respectively, P = NS). Conclusion Cardiac [O-15]H2O PET imaging is able to distinguish subendocardial from subepicardial perfusion in the myocardium of normal dimensions. Hyperaemic TPG is significantly lower in ischaemic myocardium. This technique can potentially be employed to study subendocardial perfusion impairment in more detail. However, the diagnostic accuracy of subendocardial hyperaemic perfusion and TPG appears to be limited compared with quantitative transmural MBF, warranting further study.

This study evaluates the impact of hybrid imaging on referral for invasive coronary angiography (ICA) and revascularization rates. A total of 375 patients underwent hybrid O-15-water positron emission tomography (PET)/computed tomography (CT)-based coronary angiography (CTCA) imaging for the evaluation of coronary artery disease (CAD). Downstream treatment strategy within a 60-day period after hybrid PET/CTCA imaging for ICA referral and revascularization was assessed. CTCA examinations were classified as showing no (obstructive) CAD, equivocal (borderline test result), or obstructive CAD, while the PET perfusion images were classified into normal or abnormal. On the basis of CTCA imaging, 182 (49) patients displayed no (obstructive) CAD. Only 10 (5) patients who showed no (obstructive) CAD on CTCA were referred for ICA, which were all negative. An equivocal CT study was observed in 80 (21) patients, among whom 56 (70) showed normal myocardial perfusion imaging (MPI), resulting in referral rates for ICA of 18 for normal MPI and 71 for abnormal MPI, respectively. No revascularizations were performed in the presence of normal MPI, while 59 of those with abnormal MPI were revascularized. CTCA indentified obstructive CAD in 113 (30) patients accompanied in 59 (52) patients with abnormal MPI. Referral rate for ICA was 57 for normal MPI and 88 for those with abnormal MPI, resulting in revascularization rates of 26 and 72, respectively. Hybrid O-15-water PET/CTCA imaging impacts clinical decision-making with regard to referral for ICA and revascularization procedures. Particularly, in the presence of an equivocal or abnormal CTCA, MPI could guide in the decision to refer for ICA and revascularization.

Aims There is growing evidence that coronary artery disease (CAD) affects not only the conduit epicardial coronary arteries, but also the microvascular coronary bed. Moreover, coronary microvascular dysfunction (CMVD) often precedes the stage of clinically overt epicardial CAD. Coronary artery calcium (CAC) and carotid intima-media thickness (C-IMT) measured with computed tomography (CT) and ultrasound, respectively, are among the available techniques to non-invasively assess atherosclerotic burden. An increased CAC score and C-IMT have also been associated with CMVD. It is therefore of interest to explore and compare the potential of CAC against C-IMT to predict minimal coronary vascular resistance (CVR). Methods and results We evaluated 120 patients (mean age 56 +/- 9 years, 58 men) without a documented history of CAD in whom and results obstructive CAD was excluded. All patients underwent C-IMT measurements, CAC scoring, and vasodilator stress O-15-water positron emission tomography (PET)/CT, during which the coronary flow reserve (CFR) and minimal CVR were analysed. Minimal CVR increased significantly with increasing tertiles of C-IMT (22 +/- 6, 27 +/- 11, and 28 +/- 9 mmHg mL(-1) min(-1) g(-1), P < 0.01), whereas the CFR was comparable across all C-IMT groups (P = 0.50). Minimal CVR increased significantly with an increase in CAC score (23 +/- 9, 27 +/- 8, 32 +/- 10, and 32 +/- 7 mmHg mL(-1) min(-1) g(-1). P < 0.01), whereas the CFR did not show a significant decrease with higher CAC scores (P = 0.18). Multivariable regression analysis revealed that C-IMT (P = 0.03), but not CAC, was independently associated with minimal CVR. Conclusion C-IMT, but not CAC score, independently predicts minimal CVR in patients with multiple cardiovascular risk factors and suspected of CAD.

BACKGROUND Recent studies have demonstrated improved diagnostic accuracy for detecting coronary artery disease (CAD) when myocardial blood flow (MBF) is quantified in absolute terms, but there are no uniformly accepted cutoff values for hemodynamically significant CAD. OBJECTIVES The goal of this study was to determine cutoff values for absolute MBF and to evaluate the diagnostic accuracy of quantitative [O-15]H2O positron emission tomography (PET). METHODS A total of 330 patients underwent both quantitative [O-15]H2O PET imaging and invasive coronary angiography in conjunction with fractional flow reserve measurements. A stenosis >90% and/or fractional flow reserve <= 0.80 was considered obstructive; a stenosis <30% and/or fractional flow reserve >0.80 was nonobstructive. RESULTS Hemodynamically significant CAD was diagnosed in 116 (41%) of 281 patients who fulfilled study criteria for CAD. Resting perfusion was 1.00 +/- 0.25 and 0.92 +/- 0.23 ml/min/g in regions supplied by nonstenotic and significantly stenosed vessels, respectively (p < 0.001). During stress, perfusion increased to 3.26 +/- 1.04 ml/min/g and 1.73 +/- 0.67 ml/min/g, respectively (p < 0.001). The optimal cutoff values were 2.3 and 2.5 for hyperemic MBF and myocardial flow reserve, respectively. For MBF, these cutoff values showed a sensitivity, specificity, and accuracy for detecting significant CAD of 89%, 84%, and 86%, respectively, at a per-patient level and 87%, 85%, and 85% at a per-vessel level. The corresponding myocardial flow reserve values were 86%, 72%, and 78% (per patient) and 80%, 82%, and 81% (per vessel). Age and sex significantly affected diagnostic accuracy of quantitative PET. CONCLUSIONS Quantitative MBF measurements with the use of [O-15]H2O PET provided high diagnostic performance, but both sex and age should be taken into account.

Epilepsy is a common neurological disease affecting 6 million people in Europe. Early prevention and accurate diagnosis and treatment are of importance to obtain seizure freedom. In this thesis new applications of carbon-11-labelled tracers in PET and autoradiographic studies were explored in focal epilepsy.

Patients with low-grade gliomas often experience epileptic seizures. A retrospective PET-study assessing seizure activity, metabolic rate measured with ¹¹C-methionine and other known prognostic factors was performed in patients with glioma. No correlation was found between seizure activity and uptake of methionine. The presence and termination of early seizures was a favourable prognostic factor.

Activation of the neurokinin-1 (NK1) receptor by substance P (SP) induces epileptic activity. PET with the NK1 receptor antagonist GR205171 was performed in patients with temporal lobe epilepsy (TLE) and healthy controls. In TLE patients an increased NK1 receptor availability was found in both hemispheres, most pronounced in anterior cingulate gyrus ipsilateral to seizure onset. A positive correlation between NK1 receptors and seizure frequency was observed in ipsilateral medial structures consistent with an intrinsic network using the NK1-SP receptor system for transmission of seizure activity.

The uptake of ¹⁸F-fluoro-deoxy-glucose (FDG) is related to cerebral blood flow (CBF). Previously, methods to estimate blood flow from dynamic PET data have been described. A retrospective study was conducted in 15 patients undergoing epilepsy surgery investigation, including PET with ¹¹C-FDG and ¹¹C-Flumazenil (FMZ). The dynamic FMZ dataset and pharmacokinetic modeling with a multilinear reference tissue model were used to determine images of relative CBF. Agreement between data of FDG and CBF was analyzed showing a close association between interictal brain metabolism and relative CBF.

Epilepsy often occurs after traumatic brain injuries. Changes in glia and inhibitory neuronal cells contribute to the chain of events leading to seizures. Autoradiography with ¹¹C-PK11195, ¹¹C-L-deprenyl and ¹¹C-Flumazenil in an animal model of posttraumatic epilepsy studied the temporal and spatial distribution of microglia, astrocytes and GABAergic neurons. Results showed an instant increase in microglial activity that subsequently normalized, a late formation of astrogliosis and an instant and prolonged decease in GABA binding. The model can be used to visualize pathophysiological events during the epileptogenesis.

Twelve children, all boys, aged 4 to 7 years, with a diagnosis of autistic disorder and low concentrations of spinal 6R-l-erythro-5,6,7,8-tetrahydrobiopterin (tetrahydrobiopterin) were selected to participate in a double-blind, randomized, placebo-controlled, crossover study. The children received a daily dose of 3 mg tetrahydrobiopterin per kilogram during 6 months alternating with placebo. Treatment-induced effects were assessed with the Childhood Autism Rating Scale every third month. The results showed small nonsignificant changes in the total scores of Childhood Autism Rating Scale after 3- and 6-month treatment. Post hoc analysis looking at the 3 core symptoms of autism, that is, social interaction, communication, and stereotyped behaviors, revealed a significant improvement of the social interaction score after 6 months of active treatment. In addition, a high positive correlation was found between response of the social interaction score and IQ. The results indicate a possible effect of tetrahydrobiopterin treatment.

PURPOSE: Activation of the neurokinin-1 (NK1) receptor by neuropeptide substance P (SP) induces and maintains epileptic activity in various experimental models of epilepsy. The primary objective of this study was to investigate whether neurobiological changes linked to NK1-SP receptor system are associated with hyperexcitability in patients with temporal lobe epilepsy (TLE). A secondary objective was to investigate the relationship between seizure frequency and NK1 receptor availability.

METHODS: A positron emission tomography study was conducted with the selective NK1 receptor antagonist [(11)C]GR205171 in nine patients with TLE and 18 healthy control participants. Parametric PET images were generated using the Patlak graphical method, with cerebellum as reference region. Data analyses including group comparisons were performed using statistical parametric mapping.

RESULTS: Patients with TLE showed increased NK1 receptor availability in both hemispheres with the most pronounced increase in anterior cingulate gyrus ipsilateral to seizure onset. A positive correlation between NK1 receptor availability and seizure frequency was observed in the medial temporal lobe and in the lentiform nucleus ipsilateral to the seizure onset.

CONCLUSION: Our results suggest that there is an intrinsic network using the NK1-SP receptor system for synaptic transmission and epileptiform activity in TLE.

The relationship between acetylcholinesterase (AChE) activity in the CSF and brain of patients with Alzheimer's disease (AD) was investigated in 18 mild AD patients following galantamine treatment. The first 3 months of the study had a randomized double-blind placebo-controlled design, during which 12 patients received galantamine (16-24 mg/day) and six patients placebo. This was followed by 9 months Galantamine treatment in all patients. Activities and protein levels of both the "read-through" AChE (AChE-R) and the synaptic (AChE-S) variants in CSF were assessed in parallel together with the regional brain AChE activity by C-11-PMP and PET. The AChE-S inhibition was 30-36% in CSF, which correlated well with the in vivo AChE inhibition in the brain. No significant AChE inhibition was observed in the placebo group. The increased level of the AChE-R protein was 16% higher than that of AChE-S. Both the AChE inhibition and the increased level of AChE-R protein positively correlated with the patient's performance in cognitive tests associated with visuospatial ability and attention. In conclusion, AChE levels in CSF closely mirror in vivo brain AChE levels prior to and after treatment with the cholinesterase inhibitors. A positive cognitive response seems to dependent on the AChE inhibition level, which is balanced by an increased protein level of the AChE-R variant in the patients.

OBJECTIVES:

There is an overlap regarding Pittsburgh compound B (PIB) retention in patients clinically diagnosed as Alzheimer's disease (AD) and non-AD dementia. The aim of the present study was to investigate whether there are any differences between PIB-positive and PIB-negative patients in a mixed cohort of patients with neurodegenerative dementia of mild severity regarding neuropsychological test performance and regional cerebral glucose metabolism measured with [(18)F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET).

METHODS:

Eighteen patients clinically diagnosed as probable AD or frontotemporal dementia were examined with PIB PET, FDG PET and neuropsychological tests and followed for 5-9 years in a clinical setting.

RESULTS:

The PIB-positive patients (7 out of 18) had slower psychomotor speed and more impaired visual episodic memory than the PIB-negative patients; otherwise performance did not differ between the groups. The initial clinical diagnoses were changed in one third of the patients (6 out of 18) during follow-up.

CONCLUSIONS:

The subtle differences in neuropsychological performance, the overlap of hypometabolic patterns and clinical features between AD and non-AD dementia highlight the need for amyloid biomarkers and a readiness to re-evaluate the initial diagnosis.

Objectives: There is an overlap regarding Pittsburgh Compound-B (PIB) retention in patients clinically diagnosed as Alzheimer’s disease (AD) and non-AD dementia.  The aim of the present study was to investigate whether there are any differences between PIB+ and PIB PIB- patients in a mixed cohort of patients with neurodegenerative dementia of mild severity regarding neuropsychological test performance and regional cerebral glucose metabolism measured with 18 Fluoro-2-deoxy-d-glucose (FDG) PET.

Methods: Eighteen patients clinically diagnosed as probable AD or frontotemporal dementia were examined with  PIB PET, FDG PET and neuropsychological tests and followed for 5-9 years in a clinical setting.

Results:  The PIB+ patients (7/18) had slower psychomotor speed and more impaired visual episodic memory than the PIB- patients, otherwise performance did not differ between groups. The initial clinical diagnoses were changed in one third of the patients (6/18) during follow-up.  

Conclusions: The subtle differences in neuropsychological performance, the overlap of hypometabolic patterns and clinical features between AD and non-AD dementia highlight the need of amyloid biomarkers and readiness to re-evaluate the initial diagnosis.

Background:

The positron emission tomography (PET) radiotracer Pittsburgh Compound-B (PIB) is an in vivo ligand for measuring β-amyloid (Aβ) load. Associations between PET PIB and cerebrospinal fluid (CSF) Aβ1–42 and apolipoprotein E ε4 (APOE ε4) have been observed in several studies, but the relations between PIB uptake and other biomarkers of Alzheimer’s disease (AD) are less investigated.

Method:

PET PIB, PET 18Fluoro-2-deoxy-D-glucose and different AD biomarkers were measured twice in CSF, plasma and urine 12 months apart in 10 patients with a clinical diagnosis of mild to moderate AD.

Results:

PIB retention was constant over 1 year, inversely related to low CSF Aβ1–42 (p = 0.01) and correlated positively to the numbers of the APOE ε4 allele (0, 1 or 2) (p = 0.02). There was a relation between mean PIB retention and CSF ApoE protein (r = –0.59, p = 0.07), and plasma cystatin C (r = –0.56, p = 0.09).

Conclusion:

PIB retention is strongly related to CSF Aβ1–42, and to the numbers of the APOE ε4 allele.

GABA(A) receptor alpha 5-selective inverse agonists enhance cognitive performance in pre-clinical species. However, a key aspect of the clinical development of such compounds is the demonstration that in man such compounds are devoid of the anxiogenic-like activity associated with non-selective inverse agonists such as FG 7142. The triazolophthalazine alpha 5IA (3-(5-methylisoxazol-3-yl)-6-[(1-methyl-1,2,3-triazol-4-yl) methyloxy]-1,2,4-triazolo[3,4-a]phthalazine) is an alpha 5-selective inverse agonist which enhances cognitive performance in rodents and encouragingly in human Phase I Safety and Tolerability studies it was devoid of the anxiogenic-like activity associated with FG 7142. However, in order to appropriately interpret this latter observation, it was considered important to demonstrate that the absence of anxiogenic-like activity occurs at significant levels of receptor occupancy. Consequently, the occupancy of human brain GABAA receptors was measured using [C-11]flumazenil positron emission tomography in three healthy normal young male volunteers following a single oral dose of 2 mg alpha 5IA. One hour after dosing, mean occupancy levels were 53% and this fell to 16% by 8 h post-dose, with the plasma alpha 5IA concentration corresponding to 50% occupancy being 10 ng/mL. These data clearly show that an alpha 5-selective inverse agonist is not associated with anxiogenic-like side effects at doses that give 50% occupancy.

In a previous study, patients with suspect Creutzfeldt-Jakob's disease (CJD) have been examined with Positron Emission Tomography (PET) combining N-[11C-methyl]-L-deuterodeprenyl (DED) and [(18)F] 2- fluorodeoxyglucose (FDG) in an attempt to detect astrocytosis and neuronal dysfunction, two of the hallmarks in CJD. Increased DED uptake with pronounced hypometabolism matching the areas with high DED retention was found in the fronto-parieto-occipital areas and cerebellum of patients with confirmed CJD. However, the temporal lobes did not present such a pattern. In 6 of the 15 examined patients the autopsy was performed, but a strict comparison between the PET results and the histopathology could not be done. Recently, one patient with suspect CJD was examined with PET using DED and FDG. The results of the examinations in this patient showed a pattern similar to that found in the brain of the CJD patients from the first study. The patient died shortly after the examination and an autopsy could be performed. The autopsy showed neuronal death, astrocytosis and spongiform changes in the brain. The diagnosis of definite sporadic CJD was established by the Western blot analysis, confirming the presence of the prion resistant protein (PrPres). The PET data demonstrated high DED uptake and extreme low glucose uptake in the left brain hemisphere whereas the right side was less affected. The autopsy was performed allowing the comparison between high DED uptake and the histopathological findings of reactive astrocytosis revealed by immunostaining with antibodies against glial fibrillary acid protein (GFAP). The results confirmed the presence of a pattern with high ratio DED/FDG, similar to that found in the previous study and revealing for the first time, a good correlation between high DED uptake and high density of reactive astrocytes as demonstrated by immunostaining.