18F-FDG PET/CT: an unexpected case of Huntington's disease.

BACKGROUND: Huntington's disease (HD) is a rare, genetic neurodegenerative disorder often presenting with emotional, cognitive and behavioral abnormalities before manifestation of disease defining motor symptoms. Cognitive impairment is a frequent clinical feature caused by different dementia subtypes. Imaging cortical and subcortical glucose metabolism via 18F-FDG PET/CT can help to discriminate the underlying disease. CASE PRESENTATION: The patient is a 54-year old man presenting with progressive cognitive impairment and mild orofacial dyskinesia. 18F-FDG PET/CT of the brain revealed a severe bilateral hypometabolism in the striatum. Following imaging Huntington's disease was suspected and a molecular genetic testing confirmed the diagnosis. CONCLUSIONS: Huntington's disease is a rare but important differential diagnosis of cognitive impairment, especially before motor symptoms are manifest. 18F-FDG PET is capable to show early striatal dysfunction in HD even when structural imaging is normal. We conclude that, in cases with negative family history the HD characteristic metabolic pattern can lead to the diagnosis when no other dementia-suspected changes are present.

Acute effect of intravenously applied alcohol in the human striatal and extrastriatal D2 /D3 dopamine system.

Investigations on the acute effects of alcohol in the human mesolimbic dopamine D2 /D3 receptor system have yielded conflicting results. With respect to the effects of alcohol on extrastriatal D2 /D3 dopamine receptors no investigations have been reported yet. Therefore we applied PET imaging using the postsynaptic dopamine D2 /D3 receptor ligand [18 F]fallypride addressing the question, whether intravenously applied alcohol stimulates the extrastriatal and striatal dopamine system. We measured subjective effects of alcohol and made correlation analyses with the striatal and extrastriatal D2 /D3 binding potential. Twenty-four healthy male µ-opioid receptor (OPRM1)118G allele carriers underwent a standardized intravenous and placebo alcohol administration. The subjective effects of alcohol were measured with a visual analogue scale. For the evaluation of the dopamine response we calculated the binding potential (BPND ) by using the simplified reference tissue model (SRTM). In addition, we calculated distribution volumes (target and reference regions) in 10 subjects for which metabolite corrected arterial samples were available. In the alcohol condition no significant dopamine response in terms of a reduction of BPND was observed in striatal and extrastriatal brain regions. We found a positive correlation for 'liking' alcohol and the BPND in extrastriatal brain regions (Inferior frontal cortex (IFC) (r = 0.533, p = 0.007), orbitofrontal cortex (OFC) (r = 0.416, p = 0.043) and prefrontal cortex (PFC) (r = 0.625, p = 0.001)). The acute alcohol effects on the D2 /D3 dopamine receptor binding potential of the striatal and extrastriatal system in our experiment were insignificant. A positive correlation of the subjective effect of 'liking' alcohol with cortical D2 /D3 receptors may hint at an addiction relevant trait.

Chronic alcohol intake abolishes the relationship between dopamine synthesis capacity and learning signals in the ventral striatum.

Drugs of abuse elicit dopamine release in the ventral striatum, possibly biasing dopamine-driven reinforcement learning towards drug-related reward at the expense of non-drug-related reward. Indeed, in alcohol-dependent patients, reactivity in dopaminergic target areas is shifted from non-drug-related stimuli towards drug-related stimuli. Such 'hijacked' dopamine signals may impair flexible learning from non-drug-related rewards, and thus promote craving for the drug of abuse. Here, we used functional magnetic resonance imaging to measure ventral striatal activation by reward prediction errors (RPEs) during a probabilistic reversal learning task in recently detoxified alcohol-dependent patients and healthy controls (N = 27). All participants also underwent 6-[(18) F]fluoro-DOPA positron emission tomography to assess ventral striatal dopamine synthesis capacity. Neither ventral striatal activation by RPEs nor striatal dopamine synthesis capacity differed between groups. However, ventral striatal coding of RPEs correlated inversely with craving in patients. Furthermore, we found a negative correlation between ventral striatal coding of RPEs and dopamine synthesis capacity in healthy controls, but not in alcohol-dependent patients. Moderator analyses showed that the magnitude of the association between dopamine synthesis capacity and RPE coding depended on the amount of chronic, habitual alcohol intake. Despite the relatively small sample size, a power analysis supports the reported results. Using a multimodal imaging approach, this study suggests that dopaminergic modulation of neural learning signals is disrupted in alcohol dependence in proportion to long-term alcohol intake of patients. Alcohol intake may perpetuate itself by interfering with dopaminergic modulation of neural learning signals in the ventral striatum, thus increasing craving for habitual drug intake.

Selective binding to monoamine oxidase A: in vitro and in vivo evaluation of (18)F-labeled ß-carboline derivatives.

In this study we synthesized four different (18)F-labeling precursors for the visualization of the monoamino oxidase A using harmol derivatives. Whereas two are for prosthetic group labeling using [(18)F]fluoro-d2-methyl tosylate and 2-[(18)F]fluoroethyl-tosylate, the other three precursors are for direct nucleophilic (18)F-labeling. Additionally the corresponding reference compounds were synthesized. The syntheses of [(18)F]fluoro-d2-methyl-harmol and 2-[(18)F]fluoroethyl-harmol were carried out using harmol as starting material. For direct nucleophilic (18)F-labeling of the tracers carrying oligoethyled spacers (PEG), a toluenesulfonyl leaving group was employed. The radiolabeling, purification and formulation for each tracer was optimized and evaluated in vitro and in vivo. Stability tests in human serum showed that all tracers were stable over the observation period of 60 min. µPET studies using of the synthesized tracers revealed that the tracers carrying PEG spacers showed no sufficient brain uptake. Consequently, the (18)F-fuoro alkylated tracers [(18)F]fluoro-d2-methyl-harmol and 2-[(18)F]fluoroethyl-harmol were further evaluated showing SUVs in the brain of 1.0±0.2 g/mL and 3.4±0.5 g/mL after 45 min, respectively. In blockade studies the selectivity and specificity of both tracers were demonstrated. However, for [(18)F]fluoro-d2-methyl-harmol a rapid washout from the brain was also observed. In vitro binding assays revealed that 2-[(18)F]fluoroethyl-harmol (IC50=0.54±0.06 nM) has a higher affinity than the (18)F-fluoro-d2-methylated ligand (IC50=12.2±0.6 nM), making 2-[(18)F]fluoroethyl-harmol superior to the other evaluated compounds and a promising tracer for PET imaging of the MAO A.

Construction and comparative evaluation of different activity detection methods in brain FDG-PET.

AIM: We constructed and evaluated reference brain FDG-PET databases for usage by three software programs (Computer-aided diagnosis for dementia (CAD4D), Statistical Parametric Mapping (SPM) and NEUROSTAT), which allow a user-independent detection of dementia-related hypometabolism in patients' brain FDG-PET. METHODS: Thirty-seven healthy volunteers were scanned in order to construct brain FDG reference databases, which reflect the normal, age-dependent glucose consumption in human brain, using either software. Databases were compared to each other to assess the impact of different stereotactic normalization algorithms used by either software package. In addition, performance of the new reference databases in the detection of altered glucose consumption in the brains of patients was evaluated by calculating statistical maps of regional hypometabolism in FDG-PET of 20 patients with confirmed Alzheimer's dementia (AD) and of 10 non-AD patients. Extent (hypometabolic volume referred to as cluster size) and magnitude (peak z-score) of detected hypometabolism was statistically analyzed. RESULTS: Differences between the reference databases built by CAD4D, SPM or NEUROSTAT were observed. Due to the different normalization methods, altered spatial FDG patterns were found. When analyzing patient data with the reference databases created using CAD4D, SPM or NEUROSTAT, similar characteristic clusters of hypometabolism in the same brain regions were found in the AD group with either software. However, larger z-scores were observed with CAD4D and NEUROSTAT than those reported by SPM. Better concordance with CAD4D and NEUROSTAT was achieved using the spatially normalized images of SPM and an independent z-score calculation. The three software packages identified the peak z-scores in the same brain region in 11 of 20 AD cases, and there was concordance between CAD4D and SPM in 16 AD subjects. CONCLUSION: The clinical evaluation of brain FDG-PET of 20 AD patients with either CAD4D-, SPM- or NEUROSTAT-generated databases from an identical reference dataset showed similar patterns of hypometabolism in the brain regions known to be involved in AD. The extent of hypometabolism and peak z-score appeared to be influenced by the calculation method used in each software package rather than by different spatial normalization parameters.

Central correlation of muscle sympathetic nerve activation during baroreflex unloading - a microneurography-positron emission tomography study.

The baroreceptor reflex controls spontaneous fluctuations in blood pressure. One major control variable of the baroreflex is the sympathetic vasoconstrictor activity to muscles [MSNA; burst frequency (BF) and burst incidence (BI)], which can be quantitatively assessed by microneurography. We aimed to investigate the central regions involved in baroreflex regulation of MSNA. Healthy men (mean age 25 years) participated in three experimental sessions. (i) Microneurography recordings of MSNA from the left peroneal nerve during rest and baroreflex unloading, induced by lower body negative pressure (LBNP; -40 mmHg). If MSNA could be reliably recorded throughout this procedure (n = 15), the subjects entered the positron emission tomography (PET) experiments. The two PET sessions took place in a randomised order. Cerebral glucose metabolism (18-fluorodeoxyglucose) was analysed after: (ii) baroreflex unloading (LBNP); and (iii) control condition (lying in the LBNP chamber without suction). The PET data were analysed employing SPM8. LBNP elicited a significant increase in MSNA in all successfully recorded subjects (BI: P = 0.001; F = 5.54; BF: P < 0.001; F = 36.59). As compared with the control condition, LBNP was associated with increased PET regional glucose metabolism bilaterally in the orbitofrontal cortex (OFC; BA 11, 47). Related to the rise of BF, there was increased activation of the left OFC (BA 11); related to the rise of BI there was increased activation of the brainstem corresponding to the rostral ventrolateral medulla. Our data support a role for the ventrolateral medulla and the OFC in baroreflex-mediated control of MSNA in humans.

Diagnostic Potential of Supplemental Static and Dynamic 68Ga-FAPI-46 PET for Primary 18F-FDG-Negative Pulmonary Lesions.

PET using 68Ga-labeled fibroblast activation protein (FAP) inhibitors (FAPIs) holds high potential for diagnostic imaging of various malignancies, including lung cancer (LC). However, 18F-FDG PET is still the clinical gold standard for LC imaging. Several subtypes of LC, especially lepidic LC, are frequently 18F-FDG PET-negative, which markedly hampers the assessment of single pulmonary lesions suggestive of LC. Here, we evaluated the diagnostic potential of static and dynamic 68Ga-FAPI-46 PET in the 18F-FDG-negative pulmonary lesions of 19 patients who underwent surgery or biopsy for histologic diagnosis after PET imaging. For target validation, FAP expression in lepidic LC was confirmed by FAP immunohistochemistry. Methods: Hematoxylin and eosin staining and FAP immunohistochemistry of 24 tissue sections of lepidic LC from the local tissue bank were performed and analyzed visually. Clinically, 19 patients underwent static and dynamic 68Ga-FAPI-46 PET in addition to 18F-FDG PET based on individual clinical indications. Static PET data of both examinations were analyzed by determining SUVmax, SUVmean, and tumor-to-background ratio (TBR) against the blood pool, as well as relative parameters (68Ga-FAPI-46 in relation to18F-FDG), of histologically confirmed LC and benign lesions. Time-activity curves and dynamic parameters (time to peak, slope, k 1, k 2, k 3, and k 4) were extracted from dynamic 68Ga-FAPI-46 PET data. The sensitivity and specificity of all parameters were analyzed by calculating receiver-operating-characteristic curves. Results: FAP immunohistochemistry confirmed the presence of strongly FAP-positive cancer-associated fibroblasts in lepidic LC. LC showed markedly elevated 68Ga-FAPI-46 uptake, higher TBRs, and higher 68Ga-FAPI-46-to-18F-FDG ratios for all parameters than did benign pulmonary lesions. Dynamic imaging analysis revealed differential time-activity curves for LC and benign pulmonary lesions: initially increasing time-activity curves with a decent slope were typical of LC, and steadily decreasing time-activity curve indicated benign pulmonary lesions, as was reflected by a significantly increased time to peak and significantly smaller absolute values of the slope for LC. Relative 68Ga-FAPI-46-to-18F-FDG ratios regarding SUVmax and TBR showed the highest sensitivity and specificity for the discrimination of LC from benign pulmonary lesions. Conclusion: 68Ga-FAPI-46 PET is a powerful new tool for the assessment of single 18F-FDG-negative pulmonary lesions and may optimize patient stratification in this clinical setting.

Ventral striatal prediction error signaling is associated with dopamine synthesis capacity and fluid intelligence.

Fluid intelligence represents the capacity for flexible problem solving and rapid behavioral adaptation. Rewards drive flexible behavioral adaptation, in part via a teaching signal expressed as reward prediction errors in the ventral striatum, which has been associated with phasic dopamine release in animal studies. We examined a sample of 28 healthy male adults using multimodal imaging and biological parametric mapping with (1) functional magnetic resonance imaging during a reversal learning task and (2) in a subsample of 17 subjects also with positron emission tomography using 6-[(18) F]fluoro-L-DOPA to assess dopamine synthesis capacity. Fluid intelligence was measured using a battery of nine standard neuropsychological tests. Ventral striatal BOLD correlates of reward prediction errors were positively correlated with fluid intelligence and, in the right ventral striatum, also inversely correlated with dopamine synthesis capacity (FDOPA K inapp). When exploring aspects of fluid intelligence, we observed that prediction error signaling correlates with complex attention and reasoning. These findings indicate that individual differences in the capacity for flexible problem solving relate to ventral striatal activation during reward-related learning, which in turn proved to be inversely associated with ventral striatal dopamine synthesis capacity.

Surrogate markers for cerebral blood flow correlate with [¹8F]-fallypride binding potential at dopamine D(2/3) receptors in human striatum.

Positron emission tomography (PET) with the high affinity dopamine D(2/3) receptor ligand [¹8F]-fallypride affords estimates of the binding potential (BP(ND) ) in extra-striatal regions of low receptor abundance, but the sufficient recording time for accurate measurements in striatum has been called into question. We have earlier argued that transient equilibrium measurements are obtained in striatum with [¹8F]-fallypride PET recordings of 3 h duration, which may be the practical limit for clinical investigations without interrupted scanning. However, the high extraction fraction of [¹8F]-fallypride predicts flow-dependence of tracer delivery to brain, which may be a source of variance of the apparent BP(ND) in regions of high binding. To test this prediction, we conducted a retrospective analysis of [¹8F]-fallypride PET data from a group of 50 healthy volunteers (age 18-58 years [mean ± SD: 32.6 ± 10.6), who had participated in clinical studies without arterial input measurements. We used the initial 120-s integral (AUC) of the venous confluence (VC) as a surrogate marker for cerebral blood flow (CBF) and tested for correlations between regional estimates of BP(ND) calculated by the simplified reference tissue model (SRTM) and the individual VC-AUC. The magnitude of BP(ND) in a high binding region (putamen), but not in a low binding region (thalamus) correlated positively with VC-AUC, suggesting that approximately 9% of the variance in the [¹8F]-fallypride BP(ND) in putamen can be attributed to individual differences in this surrogate marker for CBF, a contribution equal in magnitude to the effects of age on BP(ND) in putamen of the present healthy control group.

HPMA-LMA copolymer drug carriers in oncology: an in vivo PET study to assess the tumor line-specific polymer uptake and body distribution.

Polymeric drug carriers aim to selectively target tumors in combination with protecting normal tissue. In this regard polymer structure and molecular weight are key factors considering organ distribution and tumor accumulation of the polymeric drug delivery system. Four different HPMA based copolymer structures (random as well as block copolymers with lauryl methacrylate as hydrophobic block) varying in molecular weight, size and resulting architecture were analyzed in two different tumor models (AT1 prostate carcinoma and Walker-256 mammary carcinoma) in vivo. Polymers were labeled with (18)F and organ/tumor uptake was followed by µPET imaging and ex vivo biodistribution. Vascular permeability was measured by dextran extravasation and vascular density by immunohistochemistry. Cellular polymer uptake was determined in vitro using fluorescence-labeled polymers. Most strikingly, the high molecular weight HPMA-LMA random copolymer demonstrated highest tumor uptake and blood pool concentration. The molecular structure (e.g., amphiphilicity) is holding a higher impact on desired in vivo properties than polymer size. The results also revealed pronounced differences between the tumor models although vascular permeability was almost comparable. Accumulation in Walker-256 carcinomas was much higher, presumably due to a better cellular uptake in this cell line and a denser vascular network in the tumors. These investigations clearly indicate that the properties of the individual tumor determine the suitability of polymeric drug carriers. The findings also illustrate the general necessity of a preclinical screening to analyze polymer uptake for each individual patient (e.g., by noninvasive PET imaging) in order to individualize polymer-based chemotherapy.

Detection Efficacy of 68Ga-PSMA-11 PET/CT in Biochemical Recurrence of Prostate Cancer with Very Low PSA Levels: A 7-Year, Two-Center "Real-World" Experience.

In biochemical recurrence of prostate cancer (BCR), prompt tumor localization guides early treatment, potentially improving patient outcomes. Gallium-68 prostate-specific membrane antigen-11 positron emission tomography/computed tomography (68Ga-PSMA-11 PET/CT) detection rates of lesions suspicious for prostate cancer are well known to rise along with prostate-specific antigen (PSA) concentration. However, published data are limited regarding very low values (≤0.2 ng/mL). We retrospectively analyzed ~7-year "real-world" experience in this setting in a large post-prostatectomy cohort (N = 115) from two academic clinics. Altogether 44 lesions were detected in 29/115 men (25.2%) (median [minimum-maximum] 1 [1-4]/positive scan). The apparent oligometastatic disease was found in nine patients (7.8%) at PSA as low as 0.03 ng/mL. Scan positivity rates were highest when PSA was >0.15 ng/mL, PSA doubling time was ≤12 months, or the Gleason score was ≥7b (in 83 and 107 patients, respectively, with available data); these findings were statistically significant (p ≤ 0.04), except regarding PSA level (p = 0.07). Given the benefits of promptly localizing recurrence, our observations suggest the potential value of 68Ga-PSMA-11 PET/CT in the very low PSA BCR setting, especially in cases with more rapid PSA doubling time or with high-risk histology.

Ventral and dorsal streams processing visual motion perception (FDG-PET study).

BACKGROUND: Earlier functional imaging studies on visually induced self-motion perception (vection) disclosed a bilateral network of activations within primary and secondary visual cortex areas which was combined with signal decreases, i.e., deactivations, in multisensory vestibular cortex areas. This finding led to the concept of a reciprocal inhibitory interaction between the visual and vestibular systems. In order to define areas involved in special aspects of self-motion perception such as intensity and duration of the perceived circular vection (CV) or the amount of head tilt, correlation analyses of the regional cerebral glucose metabolism, rCGM (measured by fluorodeoxyglucose positron-emission tomography, FDG-PET) and these perceptual covariates were performed in 14 healthy volunteers. For analyses of the visual-vestibular interaction, the CV data were compared to a random dot motion stimulation condition (not inducing vection) and a control group at rest (no stimulation at all). RESULTS: Group subtraction analyses showed that the visual-vestibular interaction was modified during CV, i.e., the activations within the cerebellar vermis and parieto-occipital areas were enhanced. The correlation analysis between the rCGM and the intensity of visually induced vection, experienced as body tilt, showed a relationship for areas of the multisensory vestibular cortical network (inferior parietal lobule bilaterally, anterior cingulate gyrus), the medial parieto-occipital cortex, the frontal eye fields and the cerebellar vermis. The "earlier" multisensory vestibular areas like the parieto-insular vestibular cortex and the superior temporal gyrus did not appear in the latter analysis. The duration of perceived vection after stimulus stop was positively correlated with rCGM in medial temporal lobe areas bilaterally, which included the (para-)hippocampus, known to be involved in various aspects of memory processing. The amount of head tilt was found to be positively correlated with the rCGM of bilateral basal ganglia regions responsible for the control of motor function of the head. CONCLUSIONS: Our data gave further insights into subfunctions within the complex cortical network involved in the processing of visual-vestibular interaction during CV. Specific areas of this cortical network could be attributed to the ventral stream ("what" pathway) responsible for the duration after stimulus stop and to the dorsal stream ("where/how" pathway) responsible for intensity aspects.

Decline in prefrontal catecholamine synthesis explains age-related changes in cognitive speed beyond regional grey matter atrophy.

PURPOSE: Age-related decline in cognitive speed has been associated with prefrontal dopamine D1 receptor availability, but the contribution of presynaptic dopamine and noradrenaline innervation to age-related changes in cognition is unknown. METHODS: In a group of 16 healthy participants aged 22-61 years, we used PET and the radioligand FDOPA to measure catecholamine synthesis capacity (K (in) (app); millilitres per gram per minute) and the digit symbol substitution test to measure cognitive speed, a component of fluid IQ. RESULTS: Cognitive speed was associated with the magnitude of K (in) (app) in the prefrontal cortex (p < 0.0005). Both cognitive speed (p = 0.003) and FDOPA K (in) (app) (p < 0.0005) declined with age, both in a standard voxel-wise analysis and in a volume-of-interest analysis with partial volume correction, and the correlation between cognitive speed and K (in) (app) remained significant beyond the effects of age (p = 0.047). MR-based segmentation revealed that these age-related declines were not attributable to age-related alterations in grey matter density. CONCLUSION: Our findings indicate that age-related changes in the capacity of the prefrontal cortex to synthesize catecholamines, irrespective of cortical atrophy, may underlie age-related decline in cognitive speed.

Hypermetabolic Ipsilateral Supraclavicular and Axillary Lymphadenopathy: Optimal Time Point for Performing an 18F-FDG PET/CT after COVID-19 Vaccination.

Background: We aimed to evaluate the incidence of severe acute respiratory syndrome coronavirus type-2 (SARS-CoV2) vaccine-related hypermetabolic lymphadenopathy (HLA) and evaluate which time point produces the least number of false-positive findings in an 18F-2-Fluor-2-desoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT). Methods: For this retrospective, multi-center imaging study, patients with any form of SARS-CoV2 vaccination prior to an 18F-FDG-PET/CT were included between January 2021 and December 2021. Patients were divided into six groups according to the time point of vaccination prior to their 18F-FDG-PET/CT imaging, e.g., group one (0−6 days) and group six (35−80 days). As the reference standards, the SUVmax of the mediastinal blood pool (MBP) and the SUVmax contralateral reference lymph node (RL) were determined. (A) The absolute SUVmax of HLA, (B) the ratio of SUVmaxHLA/SUVmax mediastinal blood pool (rHLA/MBP), (C) the ratio SUVmax HLA vs. SUVmax contralateral reference lymph node (rHLA/RL), (D) and the incidence of HLA defined as rHLA/MBP > 1.5 were assessed. Results: Group one (days 0−6) showed the highest incidence of HLA 16/23 (70%) and rHLA/MBP (2.58 ± 2.1). All three parameters for HLA reduced statistically significantly in the comparison of Groups 1−3 (days 0−20) versus Groups 4−6 (days 21−80) (p-values < 0.001). Conclusions: If feasible, an FDG PET should be postponed by at least 3 weeks after SARS-CoV2 vaccination, especially if an accurate evaluation of axillary status is required.

Comparison of [18F]PSMA-1007 with [68Ga]Ga-PSMA-11 PET/CT in Restaging of Prostate Cancer Patients with PSA Relapse.

This study aimed to compare the diagnostic performance of [18F]PSMA-1007 positron emission tomography/computed tomography (PET/CT) (18F-PSMA) and [68Ga]Ga-PSMA-11 PET/CT (68Ga-PSMA) by identifying prostate-specific antigen (PSA) threshold levels for optimal detecting recurrent prostate cancer (PC) and to compare both methods. Retrospectively, the study included 264 patients. The performances of 18F-PSMA and 68Ga-PSMA in relation to the pre-scan PSA were assessed by receiver operating characteristic (ROC) curve. 18F-PSMA showed PC-lesions in 87.5% (112/128 patients), while 68Ga-PSMA identified them in 88.9% (121/136). For 18F-PSMA biochemical recurrent (BCR) patients treated with radical prostatectomy (78/128, patient group: F-RP), a PSA of 1.08 ng/mL was found to be the optimal cut-off level for predicting positive and negative scans (AUC = 0.821; 95%, CI: 0.710−0.932), while for prostatectomized 68Ga-PSMA BCR-patients (89/136, patient group: Ga-RP), the cut-off was 1.84 ng/mL (AUC = 0.588; 95%, CI: 0.410−0.766). In patients with PSA < 1.08 ng/mL (F-RP) 76.3% and <1.84 ng/mL (Ga-RP) 78.6% scans were positive, whereas patients with PSA ≥ 1.08 ng/mL (F-RP) or 1.84 ng/mL (Ga-RP) had positive scan results in 100% and 91.5% (p < 0.001/p = 0.085). The identified PSA thresholds for PSMA-mappable PC lesions in BCR-patients (RP) showed a better separation for 18F-PSMA with regard to the distinguishing of positive and negative PC-lesions compared to 68Ga-PSMA. However, the two PSMA PET/CT tracers gave similar overall findings.

Prefrontal and striatal dopamine D2/D3 receptors correlate with fMRI BOLD activation during stopping.

D2-like dopamine receptors in animals and humans have been shown to be linked to impulsive behaviors that are highly relevant for several psychiatric disorders. Here, we investigate the relationship between the fronto-striatal D2/D3 dopamine receptor availability and response inhibition in a selected population of healthy OPRM1 G-allele carriers. Twenty-two participants successively underwent blood-oxygen level dependent functional magnetic resonance imaging (fMRI) while performing a stop-signal task and a separate positron emission tomography (PET) scan. Striatal and extrastriatal D2/D3 dopamine receptor availability was measured using the radiotracer [18F]fallypride. Caudate D2/D3 dopamine receptor availability positively correlated with stopping-related fronto-striatal fMRI activation. In addition, right prefrontal D2/D3 dopamine receptor availability correlated positively with stopping-related striatal fMRI BOLD signal. Our study partially replicates previous findings on correlations between striatal D2/D3 dopamine receptor availability and response inhibition in a population selected for its genetic determination of dopamine response to alcohol and as a modulator of impulse control via the endogenous opioid system. We confirm the important role of D2/D3 dopamine receptor availability in the fronto-striatal neural circuit for response inhibition. Moreover, we extend previous findings suggesting that dopamine receptor availability in the right inferior frontal cortex, a crucial region of the stopping network, is also strongly associated with stopping-related striatal fMRI activity in healthy OPRM1 G-allele carriers.

Primary Staging of Prostate Cancer Patients with [18F]PSMA-1007 PET/CT Compared with [68Ga]Ga-PSMA-11 PET/CT.

BACKGROUND: Hybrid imaging with prostate-specific membrane antigen (PSMA) is gaining importance as an increasingly meaningful tool for prostate cancer (PC) diagnostics and as a guide for therapy decisions. This study aims to investigate and compare the performance of [18F]PSMA-1007 (18F-PSMA) and [68Ga]Ga-PSMA-11 positron emission tomography/computed tomography (68Ga-PSMA) in the initial staging of PC patients. METHODS: The data of 88 biopsy-proven patients were retrospectively evaluated. PSMA-avid lesions were compared with the histopathologic Gleason Score (GS) for prostate biopsies, and the results were plotted by receiver operating characteristic (ROC)-curve. Optimal maximum standardized uptake value (SUVmax) cut-off values were rated using the Youden index. RESULTS: 18F-PSMA was able to distinguish GS ≤ 7a from ≥7b with a sensitivity of 62%, specificity of 85%, positive predictive value (PPV) of 92%, and accuracy of 67% for a SUVmax of 8.95, whereas sensitivity was 54%, specificity 91%, PPV 93%, and accuracy 66% for 68Ga-PSMA (SUVmax 8.7). CONCLUSIONS: Both methods demonstrated a high concordance of detected PSMA-avid lesions with histopathologically proven PC. 18F-PSMA and 68Ga-PSMA are both suitable for the characterization of primary PC with a comparable correlation of PSMA-avid lesions with GS. Neither method showed a superior advantage. Our calculated SUVmax thresholds may represent valuable parameters in clinical use to distinguish clinically significant PC (csPC) from non-csPC.

P-glycoprotein influence on the brain uptake of a 5-HT(2A) ligand: [(18)F]MH.MZ.

BACKGROUND/AIMS: The serotonergic system, especially the 5-HT(2A) receptor, is involved in various diseases and conditions. We have recently developed a new [(18)F]-5-HT(2A) receptor ligand using an analogue, MDL 100907, as a basis for molecular imaging with positron emission tomography. This tracer, [(18)F]MH.MZ, has been shown to be an adequate tool to visualize the 5-HT(2A) receptors in vivo. However, [(18)F]altanserin, similar in chemical structure, is a substrate of efflux transporters, such as P-glycoprotein (P-gp), of the blood-brain barrier, thus limiting its availability in the central nervous system. The aim of this study was to determine whether transport by P-gp influences the distribution ratio of [(18)F]MH.MZ in the frontal cortex. METHODS: The approach was based on P-gp knockout mice which were compared with wild-type mice under several conditions. In vivo pharmacokinetic and microPET investigations were carried out. RESULTS: All analyses showed that [(18)F]MH.MZ entered the brain and was sensitive to P-gp transport. In P-gp knockout mice, brain concentrations of MH.MZ were about 5-fold higher than in wild-type animals which is reflected by a 2-fold increase in standardized uptake values of [(18)F]MH.MZ in the frontal cortex of P-gp knockout mice. CONCLUSION: Our results give evidence for a functional role of transport mechanisms at the blood-brain barrier, specifically of P-gp, and its subregional distribution. Investigation of these mechanisms will benefit the development of more efficient radioligands and drugs for molecular imaging and pharmacotherapy of the mentally ill.

Dopamine D2/D3 receptor availability and venturesomeness.

The construct of impulsivity is considered as a major trait of personality. There is growing evidence that the mesolimbic dopamine system plays an important role in the modulation of impulsivity and venturesomeness, the two key components within the impulsivity-construct. The aim of the present study was to explore an association between trait impulsivity measured with self-assessment and the dopaminergic neurotransmission as measured by positron emission tomography (PET) in a cohort of healthy male subjects. In vivo D2/D3 receptor availability was determined with [(18)F]fallypride PET in 18 non-smoking healthy subjects. The character trait impulsivity was measured using the Impulsiveness-Venturesomeness-Empathy questionnaire (I7). Image processing and statistical analysis was performed on a voxel-by-voxel basis using statistical parametric mapping (SPM) software. The I7 subscale venturesomeness correlated positively with the D2/D3 receptor availability within the left temporal cortex and the thalamus. Measures on the I7 subscale impulsiveness and empathy did not correlate with the D2/D3 receptor availability in any brain region investigated. Our results suggest the involvement of extrastriatal dopaminergic neurotransmission in venturesomeness, a component of impulsivity.

Age- and Sex-Graded Data Evaluation of Vaccination Reactions after Initial Injection of the BNT162b2 mRNA Vaccine in a Local Vaccination Center in Germany.

A high vaccination rate of older and particularly chronically ill people against coronavirus disease-2019 (COVID-19) is likely one of the most important factors in containing the pandemic. When Germany's vaccination campaign started on December 2020, vaccination prioritization was initially carried out starting with older population groups. Side effect rates in 1065 individuals who had received the first dose of the messenger ribonucleic acid (mRNA) vaccine BNT162b2 Tozinameran from BioNTech/Pfizer three weeks earlier were examined retrospectively. An age- and gender-graded data analysis showed clear age and gender differences with regard to vaccine-related adverse effects. In 77% of all individuals over 80 years of age, no local or systemic side effects were reported after the first vaccination, whereas in the age group up to 80 years, only 37% showed no side effects. In the whole study population, 64% of females and 73% of males reported no adverse effects. The initial vaccination with mRNA vaccine BNT162b2 shows an overall low profile of side effects. Particularly in those over 80 years, an extraordinarily good tolerance with equally good effectiveness is evident. The sex comparison showed that women suffer more often from adverse vaccination reactions. In order to achieve sufficient herd immunity, both age- and gender-dependent vaccination reactions and any difference in the maintenance of immunity should be considered in future vaccination strategies.