The Effects of Ecstasy (MDMA) on Brain Serotonin Transporters Are Dependent on Age-of-First Exposure in Recreational Users and Animals

Rationale and Objective

Little is known on the effects of ecstasy (MDMA, a potent 5-HT-releaser and neurotoxin) exposure on brain development in teenagers. The objective of this study was to investigate whether in humans, like previous observations made in animals, the effects of MDMA on the 5-HT system are dependent on age-of-first exposure.

Methods

5-HT transporter (SERT) densities in the frontal cortex and midbrain were assessed with [¹²³I]β-CIT single photon emission computed tomography in 33 users of ecstasy. Subjects were stratified for early-exposed users (age-at-first exposure 14–18 years; developing brain), and late-exposed users (age-at-first exposure 18–36 years; mature brain). In parallel, we investigated the effects of age experimentally with MDMA in early-exposed (adolescent) rats and late-exposed (adult) rats using the same radioligand.

Results

On average, five years after first exposure, we found a strong inverse relationship, wherein age-at-first exposure predicted 79% of the midbrain SERT variability in early (developing brain) exposed ecstasy users, whereas this was only 0.3% in late (mature brain) exposed users (p = 0.007). No such effect was observed in the frontal cortex. In rats, a significant age-BY-treatment effect (p<0.01) was observed as well, however only in the frontal cortex.

Conclusions

These age-related effects most likely reflect differences in the maturational stage of the 5-HT projection fields at age-at-first exposure and enhanced outgrowth of the 5-HT system due to 5-HT’s neurotrophic effects. Ultimately, our findings stress the need for more knowledge on the effects of pharmacotherapies that alter brain 5-HT levels in the pediatric population.     

Verbal Memory Impairment in Polydrug Ecstasy Users: A Clinical Perspective

Background

Ecstasy use has been associated with short-term and long-term memory deficits on a standard Word Learning Task (WLT). The clinical relevance of this has been debated and is currently unknown. The present study aimed at evaluating the clinical relevance of verbal memory impairment in Ecstasy users. To that end, clinical memory impairment was defined as decrement in memory performance that exceeded the cut-off value of 1.5 times the standard deviation of the average score in the healthy control sample. The primary question was whether being an Ecstasy user (E-user) was predictive of having clinically deficient memory performance compared to a healthy control group.

Methods

WLT data were pooled from four experimental MDMA studies that compared memory performance during placebo and MDMA intoxication. Control data were taken from healthy volunteers with no drug use history who completed the WLT as part of a placebo-controlled clinical trial. This resulted in a sample size of 65 E-users and 65 age- and gender-matched healthy drug-naïve controls. All participants were recruited by similar means and were tested at the same testing facilities using identical standard operating procedures. Data were analyzed using linear mixed-effects models, Bayes factor, and logistic regressions.

Results

Findings were that verbal memory performance of placebo-treated E-users did not differ from that of controls, and there was substantial evidence in favor of the null hypothesis. History of use was not predictive of memory impairment. During MDMA intoxication of E-users, verbal memory was impaired.

Conclusion

The combination of the acute and long-term findings demonstrates that, while clinically relevant memory impairment is present during intoxication, it is absent during abstinence. This suggests that use of Ecstasy/MDMA does not lead to clinically deficient memory performance in the long term. Additionally, it has to be investigated whether the current findings apply to more complex cognitive measures in diverse ‘user categories’ using a combination of genetics, imaging techniques and neuropsychological assessments.     

Physiological Slowing and Upregulation of Inhibition in Cortex Are Correlated with Behavioral Deficits in Protein Malnourished Rats

Protein malnutrition during early development has been correlated with cognitive and learning disabilities in children, but the neuronal deficits caused by long-term protein deficiency are not well understood. We exposed rats from gestation up to adulthood to a protein-deficient (PD) diet, to emulate chronic protein malnutrition in humans. The offspring exhibited significantly impaired performance on the ‘Gap-crossing’ (GC) task after reaching maturity, a behavior that has been shown to depend on normal functioning of the somatosensory cortex. The physiological state of the somatosensory cortex was examined to determine neuronal correlates of the deficits in behavior. Extracellular multi-unit recording from layer 4 (L4) neurons that receive direct thalamocortical inputs and layers 2/3 (L2/3) neurons that are dominated by intracortical connections in the whisker-barrel cortex of PD rats exhibited significantly low spontaneous activity and depressed responses to whisker stimulation. L4 neurons were more severely affected than L2/3 neurons. The response onset was significantly delayed in L4 cells. The peak response latency of L4 and L2/3 neurons was delayed significantly. In L2/3 and L4 of the barrel cortex there was a substantial increase in GAD65 (112% over controls) and much smaller increase in NMDAR1 (12-20%), suggesting enhanced inhibition in the PD cortex. These results show that chronic protein deficiency negatively affects both thalamo-cortical and cortico-cortical transmission during somatosensory information processing. The findings support the interpretation that sustained protein deficiency interferes with features of cortical sensory processing that are likely to underlie the cognitive impairments reported in humans who have suffered from prolonged protein deficiency.     

Assessment of 18FDG PET for diagnosis of pancreatic tumors

The paper examines the informational value of positron emission tomography (PET) using 18FDG in the diagnosis of malignant of neoplasms of the pancreas and in the estimation of the extent of a metastatic involvement. Forty-four patients (26 males and 18 females whose age ranged from 28 to 60 years) with histologically verified cancer of the pancreas were examined. The study was conducted in the whole body mode on an Ecat Exact 47 positron emission tomograph following 70-90 minutes of administration of 18FDG, 370-420 MBk. To assess the findings, the differential accumulation ratio (DAR) of formation/liver was calculated. The mean DAR in patients with benign and malignant pancreatic tumors was 1.17 +/- 0.064 and 4.90 +/- 0.3 (p < 0.05). There was a false positive case in a patient with an exacerbation of chronic pancreatitis in the study. A relationship was observed between the level of tumor tissue 18FDG capture and the degree of malignancy. PET scanning in the whole body mode estimates the extent of a tumorous process. The authors' data show that the liver was most commonly involved in a metastatic process (96.6%). Hence, 18FDG PET is a highly informative technique in the diagnosis of malignant pancreatic tumors and in the estimation of the extent of a metastatic process and permits a differential diagnosis between benign and malignant tumors.     

Mental Rotational Ability Is Correlated with Spatial but Not Verbal Working Memory Performance and P300 Amplitude in Males

This study investigated how both sex and individual differences in a mental rotation test (MRT) influence performance on working memory (WM). To identify the neural substrate supporting these differences, brain electrical activity was measured using the event-related potential technique. No significant sex differences were observed in a test of verbal WM, however males were significantly faster than females to respond to probe stimuli in a test of spatial WM. This difference was no longer significant after controlling for differences in MRT score, suggesting that rotational ability mediates performance in the spatial memory task for both sexes. A posterior P300 was observed in both tasks as participants encoded information into memory, however the amplitude of the P300 correlated with RT in the spatial task but not in the verbal task. Individual differences in the MRT also correlated with RT and with the amplitude of the P300, but again only in the spatial task. After splitting the analysis by sex, partial correlations controlling for MRT revealed that for males, individual differences in rotational ability completely mediated the correlation between the P300 and RT in the spatial task. This mediating effect was not observed for the female participants. The results therefore suggest a relatively stronger association in males between innate mental rotational ability, spatial memory performance, and brain electrophysiological processes supporting spatial memory.     

Prognostic Value of FDG PET Imaging in Patients with Laryngeal Cancer

Background and Purpose

To investigate the prognostic value of ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with laryngeal cancer.

Materials and Methods

The study included 51 patients of whom 30 underwent definitive radiotherapy with or without chemotherapy and 21 underwent radical surgery with or without adjuvant chemoradiation therapy. FDG uptake by both the primary lesion and the neck node was measured using the maximum standardized uptake value (SUVmax). The effects of clinicopathological factors including primary tumor SUVmax and nodal SUVmax on progression-free survival, local control, nodal progression-free survival, and distant metastasis-free survival were evaluated using the log-rank test and Cox method.

Results

The median duration of follow-up was 48.6 months (range 8 to 82.1 months). Univariate analysis showed that nodal SUVmax, N status, and tumor TNM stage were significantly associated with recurrence, whereas primary tumor SUVmax, age, treatment strategy and T status were not. Multivariate analysis demonstrated that only the nodal SUVmax was a significantly unfavorable factor for progression-free survival (p = 0.029, hazard ratio 0.54, 95% CI 0.38-0.87) and nodal progression-free survival (p = 0.023, hazard ratio 0.51, 95% CI 0.34-0.81). ROC curve analysis and log-rank test showed that patients with a high nodal SUVmax (≧4) had a significantly lower progression-free survival rate than those with a low SUVmax (<4; p<0.0001).

Conclusions

The pretreatment SUVmax of nodal disease in patients with laryngeal cancer is prognostic for recurrence.     

Accuracy of [18F]FDG PET/MRI for the Detection of Liver Metastases

Background

The aim of this study was to compare the diagnostic accuracy of [¹⁸F]FDG-PET/MRI with PET/CT for the detection of liver metastases.

Methods

32 patients with solid malignancies underwent [¹⁸F]FDG-PET/CT and subsequent PET/MRI of the liver. Two readers assessed both datasets regarding lesion characterization (benign, indeterminate, malignant), conspicuity and diagnostic confidence. An imaging follow-up (mean interval: 185±92 days) and/-or histopathological specimen served as standards of reference. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for both modalities. Accuracy was determined by calculating the area under the receiver operating characteristic (ROC) curve. Values of conspicuity and diagnostic confidence were compared using Wilcoxon-signed-rank test.

Results

The standard of reference revealed 113 liver lesions in 26 patients (malignant: n = 45; benign: n = 68). For PET/MRI a higher accuracy (PET/CT: 82.4%; PET/MRI: 96.1%; p<0.001) as well as sensitivity (67.8% vs. 92.2%, p<0.01) and NPV (82.0% vs. 95.1%, p<0.05) were observed. PET/MRI offered higher lesion conspicuity (PET/CT: 2.0±1.1 [median: 2; range 0–3]; PET/MRI: 2.8±0.5 [median: 3; range 0–3]; p<0.001) and diagnostic confidence (PET/CT: 2.0±0.8 [median: 2; range: 1–3]; PET/MRI 2.6±0.6 [median: 3; range: 1–3]; p<0.001). Furthermore, PET/MRI enabled the detection of additional PET-negative metastases (reader 1: 10; reader 2: 12).

Conclusions

PET/MRI offers higher diagnostic accuracy compared to PET/CT for the detection of liver metastases.     

Awareness of Memory Deficits in Early Stage Huntington's Disease

Patients with Huntington''s disease (HD) are often described as unaware of their motor symptoms, their behavioral disorders or their cognitive deficits, including memory. Nevertheless, because patients with Parkinson''s disease (PD) remain aware of their memory deficits despite striatal dysfunction, we hypothesize that early stage HD patients in whom degeneration predominates in the striatum can accurately judge their own memory disorders whereas more advanced patients cannot. In order to test our hypothesis, we compared subjective questionnaires of memory deficits (in HD patients and in their proxies) and objective measures of memory dysfunction in patients. Forty-six patients with manifest HD attending the out-patient department of the French National Reference Center for HD and thirty-three proxies were enrolled. We found that HD patients at an early stage of the disease (Stage 1) were more accurate than their proxies at evaluating their own memory deficits, independently from their depression level. The proxies were more influenced by patients'' functional decline rather than by patients'' memory deficits. Patients with moderate disease (Stage 2) misestimated their memory deficits compared to their proxies, whose judgment was nonetheless influenced by the severity of both functional decline and depression. Contrasting subjective memory ratings from the patients and their objective memory performance, we demonstrate that although HD patients are often reported to be unaware of their neurological, cognitive and behavioral symptoms, it is not the case for memory deficits at an early stage. Loss of awareness of memory deficits in HD is associated with the severity of the disease in terms of CAG repeats, functional decline, motor dysfunction and cognitive impairment, including memory deficits and executive dysfunction.     

Imaging of skeletal muscle function using 18FDG PET: force production, activation, and metabolism

The purpose of thisstudy was to determine whether [¹⁸F]fluorodeoxyglucose(FDG) positron emission tomography (PET) can be used to evaluate muscleforce production, create anatomic images of muscle activity, andresolve the distribution of metabolic activity within exercisingskeletal muscle. Seventeen subjects performed either elbow flexion,elbow extension, or ankle plantar flexion after intravenous injectionof FDG. PET imaging was performed subsequently, and FDG uptake wasmeasured in skeletal muscle for each task. A fivefold increase inresistance during elbow flexion increased FDG uptake in the bicepsbrachii by a factor of 4.9. Differences in relative FDG uptake weredemonstrated as exercise tasks and loads were varied, permittingdifferentiation of active muscles. The intramuscular distribution ofFDG within exercising biceps brachii varied along the transverse andlongitudinal axes of the muscle; coefficients of variation along theseaxes were 0.39 and 0.23, respectively. These findings suggest FDG PETis capable of characterizing task-specific muscle activity andmeasuring intramuscular variations of glucose metabolism withinexercising skeletal muscle.

     

Value of 18FDG PET for prediction of therapeutic response in HER2+ breast cancer: Interim analysis

¹⁸F-FDG PET is recommended for the initial staging of locally advanced breast cancer. Studies have shown the prognostic value of ¹⁸F-FDG PET for staging, but its ability to predict pathological complete response remains uncertain. Our objective was to determine the predictive value of early therapeutic evaluation by ¹⁸F-FDG PET for HER2-positive breast cancer patients. We studied a subpopulation of the prospective and multicentric French NeoTOP trial, at interim analysis. All patients were eligible for neoadjuvant chemotherapy. A ¹⁸F-FDG PET was performed at baseline and then after one cycle of neoadjuvant treatment. ¹⁸F-FDG PET were studied by three conventional methods (two visuals and one quantitative) and by textural analysis. Complete pathological response on surgical samples corresponded to grades 1/2 of Chevallier's classification and no responders corresponded to grades 3/4 of Chevallier. Pathological results were available for 21 patients. SUV_max decreased by 55% after one cycle of chemotherapy. No difference between groups was found with visuals, conventional quantitative and textural analysis of tumour uptake evaluations. Early therapeutic evaluation by ¹⁸F-FDG PET for HER2-positive breast cancer was not predictive of pathological therapeutic response after neoadjuvant treatment, with conventional study or textural analyses in this interim analysis.     

Kinetic modeling of [(18)F]FDG in skeletal muscle by PET: a four-compartment five-rate-constant model

Various modeling strategies have been developed to convert regional [(18)F]fluorodeoxyglucose ([(18)F]FDG) concentration measured by positron emission tomography (PET) to a measurement of physiological parameters. However, all the proposed models have been developed and tested mostly for brain studies. The purpose of the present study is to select the most accurate model for describing [(18)F]FDG kinetics in human skeletal muscle. The database consists of basal and hyperinsulinemic-euglycemic studies performed in normal subjects. PET data were first analyzed by an input-output modeling technique (often called spectral analysis). These results provided guidelines for developing a compartmental model. A new model with four compartments and five rate constants (5K model) emerged as the best. By accounting for plasma and extracellular and intracellular kinetics, this model allows, for the first time, PET assessment of the individual steps of [(18)F]FDG kinetics in human skeletal muscle, from plasma to extracellular space to transmembrane transport into the cell to intracellular phosphorylation. Insulin is shown to affect transport and phosphorylation but not extracellular kinetics, with the transport step becoming the main site of control. The 5K model also allows definition of the domain of validity of the classic three-compartment three- or four-rate-constant models. These models are candidates for an investigative tool to quantitatively assess insulin control on individual metabolic steps in human muscle in normal and physiopathological states.     

Prognostic Value of Lymph Node Uptake on Pretreatment F-18 FDG PET/CT in Patients with N1B Papillary Thyroid Carcinoma

Objective: The aim of this study was to investigate the prognostic value of metabolic characteristics of metastatic lymph node (LN) using pretreatment F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for patients with papillary thyroid carcinoma (PTC) and metastatic lateral LN (N1b).Methods: Ninety-six PTC patients (female:male = 72:24; median age, 44.5 years) with pathologic N1b who underwent pretreatment FDG PET/CT, total thyroidectomy, and radioactive iodine ablation were retrospectively reviewed. To predict responses to initial therapy and recurrence, clinicopathologic factors and metabolic parameters were reviewed, such as sex, age, tumor size, extranodal extension, number and ratio of metastatic LNs, serum thyroglobulin, and maximum standardized uptake value (SUVmax).Results: Among the 96 PTC patients, 81 (84.4%) were classified into the acceptable response (58 excellent; 23 indeterminate) and 15 (15.6%) into the incomplete response (8 biochemical incomplete; 7 structural incomplete) by the 2015 American Thyroid Association management guideline for differentiated thyroid carcinoma. The multivariate analysis showed that SUVmax of N1b (P = .018), pre-ablation stimulated thyroglobulin level (P = .006), and the ratio of metastatic LNs (P = .018) were related to incomplete response. The cutoff value of each variable was determined by receiver operating characteristic analysis. Nine (9.4%) patients experienced recurrences (median follow-up: 50 months). The Kaplan-Meier analysis revealed that SUVmax of N1b (cutoff value: 2.3; P = .025) and ratio of metastatic LNs (cutoff value: 0.218; P = .037) were significant prognostic factors for recurrence.Conclusion: High SUVmax of N1b cervical LN on pretreatment FDG PET/CT could predict incomplete responses to initial therapy and recurrence in patients with N1b PTC.Abbreviations: ATA = American Thyroid Association; DTC = well-differentiated thyroid carcinoma; FDG = F-18 fluorodeoxyglucose; IQR = interquartile range; LN = lymph node; N1b = metastatic lateral cervical lymph node; PET/CT = positron emission tomography/computed tomography; PTC = papillary thyroid carcinoma; RAI = radioactive iodine; ROC = receiver operating characteristic; SUVmax = maximum standardized uptake value; Tg = thyroglobulin; USG = ultrasonography     

Early detection of response to experimental chemotherapeutic Top216 with [18F]FLT and [18F]FDG PET in human ovary cancer xenografts in mice

Background

3′-deoxy-3′-[¹⁸F]fluorothymidine (¹⁸F-FLT) is a tracer used to assess cell proliferation in vivo. The aim of the study was to use ¹⁸F-FLT positron emission tomography (PET) to study treatment responses to a new anti-cancer compound. To do so, we studied early anti-proliferative effects of the experimental chemotherapy Top216 non-invasively by PET.

Methodology/Principal Findings

In vivo uptake of ¹⁸F-FLT in human ovary cancer xenografts in mice (A2780) was studied at various time points after Top216 treatment (50 mg/kg i.v. at 0 and 48 hours) was initiated. Baseline ¹⁸F-FLT scans were made before either Top216 (n = 7–10) or vehicle (n = 5–7) was injected and repeated after 2 and 6 hours and 1 and 5 days of treatment. A parallel study was made with 2′-deoxy-2′-[¹⁸F]fluoro-D-glucose (¹⁸F-FDG) (n = 8). Tracer uptake was quantified using small animal PET/CT. Imaging results were validated by tumor volume changes and gene-expression of Ki67 and TK1. Top216 (50 mg/kg 0 and 48 hours) inhibited the growth of the A2780 tumor compared to the control group (P<0.001). ¹⁸F-FLT uptake decreased significantly at 2 hours (−52%; P<0.001), 6 hours (−49%; P = 0.002) and Day 1 (−47%; P<0.001) after Top216 treatment. At Day 5 ¹⁸F-FLT uptake was comparable to uptake in the control group. Uptake of ¹⁸F-FLT was unchanged in the control group during the experiment. In the treatment group, uptake of ¹⁸F-FDG was significantly decreased at 6 hours (−21%; P = 0.003), Day 1 (−29%; P<0.001) and Day 5 (−19%; P = 0.05) compared to baseline.

Conclusions/Significance

One injection with Top216 initiated a fast and significant decrease in cell-proliferation assessable by ¹⁸F-FLT after 2 hours. The early reductions in tumor cell proliferation preceded changes in tumor size. Our data indicate that ¹⁸F-FLT PET is promising for the early non-invasive assessment of chemotherapy effects in both drug development and for tailoring therapy in patients.     

Combination of [68Ga]Ga-PSMA PET/CT and [18F]FDG PET/CT in demonstrating dedifferentiation in castration-resistant prostate cancer

Aim of the studyIn this study, we aimed to determine the factors affecting increased glucose metabolism, which is one of the dedifferentiation mechanisms, by using [¹⁸F]FDG and [⁶⁸Ga]Ga-PSMA PET/CT in patients with castration-resistant prostate cancer (CRPC).Materials and methodNinety-three patients with CRPC were included in the study. Gleason score (GS), and total PSA and free PSA levels of the patients were recorded. Patient- and organ-based evaluations were performed according to the lesion uptakes as follows: score 0: PSMA (-) FDG (-), score 1: PSMA (+) FDG (-), score 2: PSMA (+) FDG (+) (FDG < PSMA), score 3: PSMA (+) FDG (+) (FDG = PSMA), score 4: PSMA (+) FDG (+) (FDG > PSMA), and score 5: PSMA (-) FDG (+). scores 1 and 2 were classified as group 1, and scores 3 to 5 were classified as group 2.ResultsThe median age of our patients was 70 (51–88) years. Eighty-eight patients (94.6%) were PSMA-positive, 78 patients (83.8%) were FDG-positive, and 89 patients (95.6%) were or PSMA or FDG positive. When the two groups were compared in terms of patient-based parameters, the median age and GS were found to be significantly higher in group 2. ROC analyses revealed that age and GS were significant in predicting group 2.ConclusionSince glucose metabolism can increase in CRPC patients with advanced age and high GS, we recommend combining [¹⁸F]FDG PET/CT with [⁶⁸Ga]Ga-PSMA PET/CT in routine clinical practice in order to identify this patient subset and refer them to additional therapies.     

轻度认知损伤患者的联系记忆损伤特征

遗忘型轻度认知损伤患者(aMCI)在项目记忆和联系记忆上都有损伤．本文通过临床记忆量表中的项目记忆和联系记忆测验,研究aMCI的联系记忆是否比项目记忆有更显著的损伤．另外,通过分析配对联想学习测验,进一步研究aMCI联系记忆损伤的特点．25名aMCI和28名健康老人参与了两个联系记忆测验(配对联想学习测验和联想回忆测验)和两个项目记忆测验(图像自由回忆和无意义图形再认),aMCI患者在联系记忆测验上表现出了更显著的损伤,即使控制了项目记忆的损伤,aMCI的联系记忆仍然比健康老人显著降低．另外,ROC分析表明联系记忆测验比项目记忆测验对aMCI病人有更高的区分度．对配对联想学习测验的分析表明,相对于健康老人,aMCI患者在记忆有语言联系的词对要比记忆无语义联系的词对更为困难．本研究进一步表明aMCI患者的联系记忆比项目记忆有更大的损伤．相对于健康老人,aMCI患者不仅难以在两个无关项目间创建记忆连接,而且在有效利用项目间本身的语义联系方面存在更大的损伤．联系记忆测验比项目记忆测验对aMCI患者有更高的区分度．在神经心理评估中增加联系记忆测验,能更加有效地识别aMCI患者．     

Nandrolone Supplementation Promotes AMPK Activation and Divergent 18[FDG] PET Brain Connectivity in Adult and Aged Mice

Neurochemical Research - Decreased anabolic androgen levels are followed by impaired brain energy support and sensing with loss of neural connectivity during physiological aging, providing a...