PSMA-1007 Uptake in Ganglia of the Sympathetic Trunk and Its Intra-individual Reproducibility.

AIM/PURPOSE: 18F-labeled PSMA ligands offer various advantages as PET tracers over 68Ga-labeled PSMA counterparts. Especially, an improved spatial resolution leads to improved detection rates of smaller prostate cancer (PCa) lesions. However, physiological PSMA uptake of ganglia of the sympathetic trunk can be quickly misinterpreted as possible PSMA-positive lymph node metastases. The aim of this retrospective study is to investigate [18F]PSMA-1007 uptake and its intra-individual reproducibility in ganglia of the sympathetic trunk. METHODS: We retrospectively included 28 consecutive patients (median age 69 ± 9 with a range of 49-90) with biochemical recurrence of PCa who underwent [18F]PSMA-1007 PET/CT scan and, accordingly, a follow-up examination between August 2018 and August 2021. Cervical, coeliac, and sacral ganglia were identified on the iterative PET reconstructions and correlated with CT component. Tracer uptake of ganglia was determined by measuring SUVmax and SUVmean values. Anatomical position of the ganglia in relation to adjacent vertebral bodies were noted. Statistical analyses were conducted using two-way repeated measures ANOVA and descriptive statistics. RESULTS: The highest [18F]PSMA-1007 uptake was found in coeliac ganglia followed by cervical and sacral ganglia. The SUVmax in coeliac ganglia was 3.13 ± 0.85 (follow-up scan 3.11 ± 0.93), in cervical ganglia 2.73 ± 0.69 (follow-up scan 2.67 ± 0.74), and in sacral ganglia 1.67 ± 0.50 (follow-up scan 1.64 ± 0.52). The SUVmean in coeliac ganglia was 2.28 ± 0.64 (follow-up scan 2.28 ± 0.66), in cervical ganglia 1.62 ± 0.43 (follow-up scan 1.61 ± 0.43) and in sacral ganglia 1.15 ± 0.33 (follow-up scan 1.12 ± 0.34). In a given ganglion station, there was no statistically significant difference of SUVmax or SUVmean values between baseline and follow-up scans. CONCLUSIONS: The first systematically described physiological [18F]PSMA-1007 uptake in ganglia of the sympathetic trunk showed a low variability of SUVmax or SUVmean and a good intra-individual reproducibility of [18F]PSMA-1007 uptake in follow-up scans. These findings might improve and guide the differentiation of ganglia from possible malignant lesions.

Distinguishing Benign and Malignant Findings on [68 Ga]-FAPI PET/CT Based on Quantitative SUV Measurements.

AIM/PURPOSE: Fibroblast activation protein (FAP) is overexpressed by cancer-associated fibroblasts. However, activated fibroblasts have been shown to play a significant role also in certain benign conditions such as wound healing or chronic inflammation. Therefore, the current study aimed to identify whether FAPI uptake might differ between malignant lesions and benign conditions. MATERIAL AND METHODS: We retrospectively analyzed 155 patients with various cancer types who received [68 Ga]-FAPI-04/02-PET/CT between July 2017 and March 2020. SUVmax, SUVmean, and lesion-to-background ratios (LBR) of FAPI uptake were measured in benign processes compared to malignant lesions (primary and/or 2 exemplary metastases). In addition, receiver operating characteristic (ROC) curve analysis was conducted to compare the predictive capabilities of semiquantitative PET/CT parameters. Furthermore, the sensitivity, specificity, optimal cutoff value, and 95% confidence interval (CI) were determined for each parameter. RESULTS: Benign lesions exhibited significantly lower FAPI uptake compared to malignant lesions (mean SUVmax benign vs. malignant: 4.2 vs. 10.6; p < 0.001). In ROC analysis, cutoff values of these lesions (benign vs. malignant) were established based on SUVmax, SUVmean, and LBR. The SUVmax cutoff value for all lesions was 5.5 and the corresponding sensitivity, specificity, accuracy, and AUC were 78.8%, 85.1%, 82.0%, and 0.89%, respectively. CONCLUSION: Our aim was to systematically analyze the pattern of FAPI uptake in benign and malignant processes. This investigation demonstrates that FAPI uptake might be useful to differentiate malignant and benign findings due to different patho-physiological origins.

Head-to-head Intra-individual Comparison of [68Ga]-FAPI and [18F]-FDG PET/CT in Patients with Bladder Cancer.

AIM/PURPOSE: Fibroblast activation protein-(FAP)-ligands, a novel class of tracers for PET/CT imaging, demonstrated promising results in previous studies in various malignancies compared to standard [18F]FDG PET/CT. 68Ga-labeled fibroblast activation protein inhibitor-([68Ga]Ga-DOTA-FAPI)-PET/CT impresses with sharp contrasts in terms of high tumor uptake and low background noise leading to clear delineation. [18F]FDG PET/CT has limited accuracy in bladder cancer due to high background signal. Therefore, we sought to evaluate the diagnostic potential of [68Ga]FAPI in patients with bladder cancer. MATERIAL AND METHODS: This retrospective analysis consisted of 8 patients (median age 66), 7 of whom underwent both [68Ga]FAPI and [18F]FDG PET/CT scans with a median time interval of 5 days (range 1-20 days). Quantification of tracer uptake was determined with SUVmax and SUVmean. Furthermore, the tumor-to-background ratio (TBR) was derived by dividing the SUVmax of tumor lesions by the SUVmax of adipose tissue, skeletal muscle, and blood pool. RESULTS: Overall, 31 metastases were detected in five patients including lymph node metastases (n = 23), bone metastases (n = 4), lung metastases (n = 3), and a peritoneal metastasis (n = 1). In one patient, [68Ga]FAPI demonstrated significant uptake in the primary tumor located in the bladder wall. [68Ga]FAPI-PET/CT demonstrated significantly higher uptake compared to [18F]FDG PET/CT with higher mean SUVmax (8.2 vs. 4.6; p = 0.01). Furthermore, [68Ga]FAPI detected additional 30% (n = 9) lesions, missed by [18F]FDG. TBR demonstrated favorable uptake for [68Ga]FAPI in comparison to [18F]FDG. Significant differences were determined with regard to metastasis/blood pool ([68Ga]FAPI 5.3 vs [18F]FDG 1.9; p = 0.001). CONCLUSION: [68Ga]FAPI-PET/CT is a promising diagnostic radioligand for patients with bladder cancer. This first described analysis of FAP-ligand in bladder cancer revealed superiority over [18F]FDG in a small patient cohort. Thus, this so far assumed potential has to be confirmed and extended by larger and prospective studies.

In vivo imaging neurotransmitter function. The rat 6-hydroxydopamine model and its relevance for human Parkinson's disease.

This article gives an overview of those small animal imaging studies which have been conducted on neurotransmitter function in the rat 6-hydoxydopamine (6-OHDA) model of Parkinson's disease, and discusses findings with respect to the outcome of clinical studies on Parkinsonian patients.

Neural traffic as voxel-based measure of cerebral functional connectivity in fMRI.

To access functional connectivity by in vivo brain imaging voxel-by-voxel, we developed a novel approach named neural traffic (NT). NT depicts the intensity of functional connectivity on a voxel-by-voxel basis in the whole brain. Functional magnetic resonance imaging (fMRI) experiments were carried out on eight individuals during either hearing or viewing words. The blood oxygen level dependant (BOLD) signal was taken as measure of neural activity. For each voxel, functional connectivity with all other brain voxels was determined by calculating Pearson correlation coefficients at two connectivity thresholds (r=0.35 and 0.65). Then, NT images were derived by counting the number of suprathreshold connections for each individual voxel. Calculations based on random networks indicate that statistically reliable NT images can be derived in individuals. With regard to group analysis, at r=0.35 NT images are similar though not identical with the first component of principal component analysis (PCA), displaying a widespread but not ubiquitous pattern of functionally connected cortical areas. At r=0.65, NT group images display functional connectivity confined to circumscribed cortical regions which reach beyond the corresponding primary sensory areas, their known associated areas and the default network. In conclusion, NT goes beyond the approach of correlating the BOLD signal with the external stimulus-presentation time course by computing linear functional connectivity between all brain voxels based on any BOLD time course. First results demonstrate that the NT approach is likely - on an individual base - to reveal novel cortical and subcortical connectivities involved in stimulus processing.

Neural correlates of subliminal and supraliminal letter processing--an event-related fMRI study.

One problem of interpreting research on subconscious processing is the possibility that participants are weakly conscious of the stimuli. Here, we compared the fMRI BOLD response in healthy adults to clearly visible single letters (supraliminal presentation) with the response to letters presented in the absence of any behavioural evidence of visibility (subliminal presentation). No letter catch trials served as a control condition. Forced-choice responses did not differ from chance when letter-to-background contrast was low, whereas they were almost 100% correct when contrast was high. A comparison of fMRI BOLD signals for supraliminal and subliminal letters with the control trials revealed a signal increase in left BA 37 (fusiform gyrus). Comparison of supraliminal with subliminal letters showed a significant increase in the right inferior frontal gyrus (BA 44, partly extending to BA 9 and BA 45, as well as BA 46). Finally, a comparison of subliminal with supraliminal letters showed increases in the left middle temporal gyrus (BA 21) and the right extrastriate cortex (BA 19).

Distribution of 5HT2A receptors in the human brain: comparison of data in vivo and post mortem.

AIM: The study presented here firstly compares the distribution of the binding potential of the serotonin-5HT2A receptor as measured in vivo with data of receptor density taken from literature. Secondly, the sensitivity of the method to detect gradual differences in receptor densities is evaluated. METHODS: Positron emission tomography (PET) studies were carried out in 6 healthy volunteers using the selective serotonin-5HT2A ligand 18F-altanserin. The binding potential was quantified in 12 regions using Logan's graphical method and the equilibrium method. These data were compared to the distribution of receptor density as taken from literature. RESULTS: The binding data in vivo correlated to autoradiography data (post mortem) with r = 0.83 (Pearson regression coefficient; p < 0.0001). A difference in the receptor density between two regions could be detected with p < 0.05 when it amounted at least to 18%. CONCLUSION: This study demonstrates a good agreement between in vivo data obtained with 18F-altanserin and PET in healthy volunteers and the true autoradiographically determined distribution of 5HT2A receptors in human brains. The in vivo method seems to be sensitive enough to detect changes in receptor density of more than 18%.

Imaging of striatal dopamine D(2) receptors with a PET system for small laboratory animals in comparison with storage phosphor autoradiography: a validation study with (18)F-(N-methyl)benperidol.

UNLABELLED: Several groups have developed high-resolution PET systems and shown the feasibility of in vivo studies on small laboratory animals. In this investigation, one of these systems was validated for the performance of receptor imaging studies. For this, the radiotracer concentrations obtained in the same animals with PET and with autoradiography were quantified, and the correspondence between both methods was assessed by means of correlation analysis. METHODS: Striatal radioactivity was measured in 10 Sprague-Dawley rats after injection of 60 +/- 10 MBq of the dopamine D(2) receptor ligand (18)F-(N-methyl)benperidol in 6 time frames of 6 min each. On completion of the scans, animals were killed, and their brains were removed and sectioned using a cryostat microtome. Coronal slices were subjected to storage phosphor autoradiography with BaFBr:Eu(2+)-coated imaging plates. Striatal radioactivity was quantified in both modalities using region-of-interest analysis and activity standards. RESULTS: After partial-volume correction, the median of striatal radioactivity concentration measured with PET was 0.40 MBq/cm(3) (25th percentile, 0.32; 75th percentile, 0.44). Radioactivity concentrations determined by means of storage phosphor autoradiography amounted to 0.42 MBq/cm(3) (25th percentile, 0.24; 75th percentile, 0.51). Correlation of striatal radioactivity values yielded a Pearson correlation coefficient of 0.818 (P = 0.002). Radioactivity accumulation in Harder's glands led to an overestimation of striatal activity concentrations by approximately 5%. The median of striatal radioactivity concentration after spillover correction decreased slightly to 0.38 MBq/cm(3) (25th percentile, 0.30; 75th percentile, 0.43). Correlation of striatal radioactivity values after spillover correction yielded a Pearson correlation coefficient of 0.824 (P = 0.002). CONCLUSION: The results show a significant positive correlation between radioactivity values obtained with PET and storage phosphor autoradiography used as the gold standard. Because we applied a selective dopamine D(2) receptor radioligand and because radioactivity concentrations could be reliably quantified in the target region, we may infer that in vivo receptor binding studies will be possible in small laboratory animals.

Modulation of the neuronal circuitry subserving working memory in healthy human subjects by repetitive transcranial magnetic stimulation.

We studied the effect of repetitive transcranial magnetic stimulation (rTMS) on changes in regional cerebral blood flow (rCBF) as revealed by positron emission tomography (PET) while subjects performed a 2-back verbal working memory (WM) task. rTMS to the right or left dorsolateral prefrontal cortex (DLPFC), but not to the midline frontal cortex, significantly worsened performance in the WM task while inducing significant reductions in rCBF at the stimulation site and in distant brain regions. These results for the first time demonstrate the ability of rTMS to produce temporary functional lesions in elements of a neuronal network thus changing its distributed activations and resulting in behavioral consequences.

Diffuse cortical reduction of neuronal activity in unipolar major depression: a retrospective analysis of 337 patients and 321 controls.

Reduction of neuronal activity in frontocortical and limbic circuits is considered a characteristic of depression. We aimed to test this hypothesis by pooling all available data from experimental literature. All investigations were included comparing regional cerebral blood flow (rCBF) or glucose metabolism (rCMRGlc) between acutely depressed unipolar major depressive patients and healthy controls. For cortical and subcortical regions we computed the percentage difference between depressives (n = 337) and controls (n = 321). In patients with unipolar major depression rCBF and rCMRGlc were lowered in left (-4.4%, P = 0.022) and right frontal (-3.2%, P = 0.053), left (-1.7%, P = 0.061) and right temporal (-3.0%, P=0.003), left (-6.5%, P = 0.002), and right parietal (-8.8%, P=0.001), and left (-6.6%, P = 0.083) and right occipital cortex (-4.2%, P = 0.02). Moreover, there were reductions in left (-6.3%, P = 0.029) and right basal ganglia (-4.8%, P = 0.002), left (-3.4%, P = 0.114) and right thalamus (-3.1%, P = 0.036), and left limbic system (-2.2%, P = 0.127). Parameters were increased by 1.0% (P = 0.714) only in the right limbic system. There were no hemispheric asymmetries (P > 0.05). Moreover, there was no indication for an anterior-posterior gradient (P > 0.05), and thus no 'hypofrontality'. In contrast to the current view, the data indicate a diffuse cortical rather than regionalized reduction of neuronal activity in unipolar major depression.

Quantification of glucose transport and phosphorylation in human skeletal muscle using FDG PET.

UNLABELLED: PET with 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) is used for quantifying glucose metabolism in brain and myocardium in vivo. We developed and validated a similar procedure for the quantification of the two initial steps of glucose metabolism in skeletal muscle in vivo. METHODS: The measurement protocol was first optimized by computer simulations. In addition to the accuracy in sampling plasma input and tissue time-activity curves, precise determination of the fractional blood volume, that is, the extracellular tissue volume fraction, plays a key role in correctness of the determined model constants. The optimized protocol was subsequently used to estimate transmembrane muscular glucose transport and hexokinase activity in six human subjects with normal or altered glucose utilization. PET was performed during the steady state of an euglycemic hyperinsulinemic clamp. RESULTS: A three-compartment model provides a better description of the experimental data than a two- or four-compartment model. Glucose clearance from the extracellular compartment into the skeletal muscle cell (K1) ranges from 0.024 to 0.093 mL/g/min. The intracellular glucose phosphorylation rate (k3) varies between 0.030 and 0.142 min(-1). The regional muscular glucose utilization, as calculated from the determined model parameters, lies between 10.7 and 83.3 micromol/kg/min and correlates with the whole-body glucose utilization as independently determined (R2 = 0.83; P < or = 0.01). CONCLUSION: We demonstrate by computer simulations that a three-compartment model can be used to characterize the first two steps of glucose metabolism in skeletal muscle. An optimized measurement protocol is developed and applied to experimental data. This experimental approach should be appropriate to test whether glucose transport or hexokinase activity is altered in disorders of muscular glucose utilization.

Infecçäo causada por Mycobacterium tuberculosis com resistência primária a múltiplas drogas: relato de caso em paciente com AIDS / Infection caused by Mycobacterium tuberculosis with primary resistance to multiple drugs: a case report of a patient with AIDS

Mycobacterium tuberculosis, primariamente resistente a múltiplas drogas, é problema de crescente importância nos Estados Unidos. No Brasil, näo existem relatos, pelo menos em literatura formal, de infecçäo por este patógeno. Relato de caso. Os autores relatam caso de paciente do sexo masculino que teve diagnóstico de tuberculose ganglionar cervical por meio de baciloscopia. Adicionalmente, anti-HIV feito por método ELISA resultou positivo. O paciente iniciou esquema terapêutico com isoniazida, rifampicina e pirazinamida. Segundo o paciente e seus familiares, os medicamentos foram administrados corretamente, mas näo foi observada melhora clínica. Após 75 dias de tratamento, o paciente foi internado no Hospital do Servidor Público Estadual de Säo Paulo com piora clínica caracterizada por aumento de gânglio submandibular, insuficiência respiratória e dor abdominal, vindo a falecer seis dias após a admissäo. Cultura do aspirado ganglionar, colhida no dia da internaçäo, mostrou crescimento de M. tuberculosis sensível ao etambutol e resistente à isoniazida, rifampicina, pirazinamida, etionamida e estreptomicina. Discussäo. O isolamento de M. tuberculosis multirresistente, mesmo que em paciente com forma extra-pulmonar da doença, traz à tona discussäo da necessidade da prevalência do patógeno em nosso meio mediante realizaçäo de cultura e antibiograma, e ressalta problemas inerentes à MTB-MDR, como a alta letalidade em pacientes com infecçäo clinicamente manifesta e a transmissäo intra-hospitalar, já demonstrada em outros países. É discutida a necessidade de cumprimento rigoroso das medidas de isolamento

[Infection caused by Mycobacterium tuberculosis with primary resistance to multiple drugs: a case report of a patient with AIDS]. / Infecção causada por Mycobacterium tuberculosis com resistência primária a múltiplas drogas: relato de um caso em paciente com AIDS.

Primary multidrug-resistant Mycobacterium tuberculosis is an important problem in the United States. There is no report in formal literature of this pathogen in Brazilian patients. CASE REPORT--We report a case of ganglionar tuberculosis diagnosed by acid-fast smears in a male, HIV positive patient. Mode of acquisition of HIV was not determined. Treatment was started, and isoniazid, rifampicin and pyrazinamide were prescribed. The patient and his family reported strict adherence to therapy, but no improvement was observed. After 75 days, the patient was admitted in our hospital because of clinical worsening. Clinical features were the presence of large submandibular and axillar lymph nodes, respiratory insufficiency and complains of abdominal pain. He died six days after admission. Culture obtained from the ganglionar aspirate disclosed M. tuberculosis susceptible to ethambutol, but resistant to isoniazid, rifampicin, pyrazinamide, ethionamide and streptomycin. DISCUSSION--Although this was a case of extrapulmonary tuberculosis, there is a concern about multidrug-resistant tuberculosis, that has been poorly evaluated in Brazil. Since high lethality and intrahospital transmission have been reported, we discuss the need of performing culture and antibiogram in suspected cases, and the prevention of the spread of M. tuberculosis to patients and health-care workers through the strict adherence to the isolation practices.