Cortical Amyloid Burden Relates to Basal Forebrain Volume in Subjective Cognitive Decline.

BACKGROUND: Atrophy of cholinergic basal forebrain (BF) nuclei is a frequent finding in magnetic resonance imaging (MRI) volumetry studies that examined patients with prodromal or clinical Alzheimer's disease (AD), but less clear for individuals in earlier stages of the clinical AD continuum. OBJECTIVE: To examine BF volume reductions in subjective cognitive decline (SCD) participants with AD pathologic changes. METHODS: The present study compared MRI-based BF volume measurements in age- and sex-matched samples of N = 24 amyloid-positive and N = 24 amyloid-negative SCD individuals, based on binary visual ratings of Florbetaben positron emission tomography (PET) measurements. Additionally, we assessed associations of BF volume with cortical amyloid burden, based on semiquantitative Centiloid (CL) analyses. RESULTS: Group differences approached significance for BF total volume (p = 0.061) and the Ch4 subregion (p = 0.059) only, showing the expected relative volume reductions for the amyloid-positive subgroup. There were also significant inverse correlations between BF volumes and CL values, which again were most robust for BF total volume and the Ch4 subregion. CONCLUSIONS: The results are consistent with the hypothesis that amyloid-positive SCD individuals, which are considered to represent a transitional stage on the clinical AD continuum, already show incipient alterations of BF integrity. The negative association with a continuous measure of cortical amyloid burden also suggests that this may reflect an incremental process. Yet, further research is needed to evaluate whether BF changes already emerge at "grey zone" levels of amyloid accumulation, before amyloidosis is reliably detected by PET visual readings.

Altered limbic functional connectivity in individuals with subjective cognitive decline: Converging and diverging findings across Chinese and German cohorts.

INTRODUCTION: It remains unclear whether functional brain networks are consistently altered in individuals with subjective cognitive decline (SCD) of diverse ethnic and cultural backgrounds and whether the network alterations are associated with an amyloid burden. METHODS: Cross-sectional resting-state functional magnetic resonance imaging connectivity (FC) and amyloid-positron emission tomography (PET) data from the Chinese Sino Longitudinal Study on Cognitive Decline and German DZNE Longitudinal Cognitive Impairment and Dementia cohorts were analyzed. RESULTS: Limbic FC, particularly hippocampal connectivity with right insula, was consistently higher in SCD than in controls, and correlated with SCD-plus features. Smaller SCD subcohorts with PET showed inconsistent amyloid positivity rates and FC-amyloid associations across cohorts. DISCUSSION: Our results suggest an early adaptation of the limbic network in SCD, which may reflect increased awareness of cognitive decline, irrespective of amyloid pathology. Different amyloid positivity rates may indicate a heterogeneous underlying etiology in Eastern and Western SCD cohorts when applying current research criteria. Future studies should identify culture-specific features to enrich preclinical Alzheimer's disease in non-Western populations. HIGHLIGHTS: Common limbic hyperconnectivity across Chinese and German subjective cognitive decline (SCD) cohorts was observed. Limbic hyperconnectivity may reflect awareness of cognition, irrespective of amyloid load. Further cross-cultural harmonization of SCD regarding Alzheimer's disease pathology is required.

Chronic Pleural Effusion in Ventriculoperitoneal Shunt due to Diaphragmatic CSF Fistula: Report of a Case Treated by Endoscopic Choroid Plexus Coagulation and Literature Review.

INTRODUCTION: Chronic pleural cerebrospinal fluid (CSF) effusion is a rare complication after ventriculoperitoneal (VP) shunt insertion and only 18 cases in children and adults have been described so far without catheter dislocation to the intrathoracic cavity. CASE PRESENTATION: We report on a 4-year-old girl with a complex history of underlying neurogenetic disorder, a hypoxic-ischemic encephalopathy after influenza A infection with septic shock and severe acute respiratory distress syndrome, followed by meningitis at the age of 10 months. In consequence, she developed a severe cerebral atrophy and post-meningitic hydrocephalus requiring placement of a VP shunt. At age 4, she was admitted with community-acquired mycoplasma pneumonia and developed increasing pleural effusions leading to severe respiratory distress and requiring continuous chest tube drainage (up to 1,000-1,400 mL/day) that could not be weaned. ß trace protein, in CSF present at concentrations >6 mg/L, was found in the pleural fluid at low concentrations of 2.7 mg/L. An abdomino-thoracic CSF fistula was finally proven by single photon emission computerized tomography combined with low-dose computer tomography. After shunt externalization, the pleural effusion stopped and the chest tube was removed. CSF production rate remains high above 500 mL/24 h. An atrial CSF shunt could not be placed, since a hemodynamically relevant atrial septum defect with frail circulatory balance would not have tolerated the large CSF volumes. Therefore, she underwent a total bilateral endoscopic choroid plexus laser coagulation (CPC) within the lateral ventricles via bi-occipital burr holes. Postoperatively CSF production rate went close to 0 mL and after external ventricular drain removal no signs and symptoms of hydrocephalus developed during a follow-up of now 2.5 years. CONCLUSION: In summary, pleural effusions in patients with VP shunt can rarely be caused by an abdomino-thoracic fistula, with non-elevated ß-trace protein in the pleural fluid. The majority of reported cases in literature were treated by ventriculoatrial shunt. This is the 2nd reported case, which has been successfully treated by radical CPC alone including the temporal horn choroid plexus, making the child shunt independent.

Estimating uncertainty in read-out patterns: Application to controls-based denoising and voxel-based morphometry patterns in neurodegenerative and neuropsychiatric diseases.

Quantifying pathology-related patterns in patient data with pattern expression score (PES) is a standard approach in medical image analysis. In order to estimate the PES error, we here propose to express the uncertainty contained in read-out patterns in terms of the expected squared Euclidean distance between the read-out pattern and the unknown "true" pattern (squared standard error of the read-out pattern, SE2 ). Using SE2 , we predicted and optimized the net benefit (NBe) of the recently suggested method controls-based denoising (CODE) by weighting patterns of nonpathological variance (NPV). Multi-center MRI (1192 patients with various neurodegenerative and neuropsychiatric diseases, 1832 healthy controls) were analysed with voxel-based morphometry. For each pathology, accounting for SE2 , NBe correctly predicted classification improvement and allowed to optimize NPV pattern weights. Using these weights, CODE improved classification performances in all but one analyses, for example, for prediction of conversion to Alzheimer's disease (AUC 0.81 vs. 0.75, p = .01), diagnosis of autism (AUC 0.66 vs. 0.60, p < .001), and of major depressive disorder (AUC 0.62 vs. 0.50, p = .03). We conclude that the degree of uncertainty in a read-out pattern should generally be reported in PES-based analyses and suggest using weighted CODE as a complement to PES-based analyses.

Dose escalation to hypoxic subvolumes in head and neck cancer: A randomized phase II study using dynamic [18F]FMISO PET/CT.

BACKGROUND AND PURPOSE: Tumor hypoxia is a major cause of resistance to radiochemotherapy in locally advanced head-and-neck cancer (LASCCHN). We present results of a randomized phase II trial on hypoxia dose escalation (DE) in LASCCHN based on dynamic [18F]FMISO (dynFMISO) positron emission tomography (PET). The purpose was to confirm the prognostic value of hypoxia PET and assess feasibility, toxicity and efficacy of hypoxia-DE. MATERIALS AND METHODS: Patients with LASCCHN underwent baseline dynFMISO PET/CT. Hypoxic volumes (HV) were derived from dynFMISO data. Patients with hypoxic tumors (HV > 0) were randomized into standard radiotherapy (ST: 70Gy/35fx) or dose escalation (DE: 77Gy/35fx) to the HV. Patients with non-hypoxic tumors were treated with ST. After a minimum follow-up of 2 years feasibility, acute/late toxicity and local control (LC) were analyzed. RESULTS: The study was closed prematurely due to slow accrual. Between 2009 and 2017, 53 patients were enrolled, 39 (74%) had hypoxic tumors and were randomized into ST or DE. For non-hypoxic patients, 100% 5-year LC was observed compared to 74% in patients with hypoxic tumors (p = 0.039). The difference in 5-year LC between DE (16/19) and ST (10/17) was 25%, p = 0.150. No relevant differences related to acute and late toxicities between the groups were observed. CONCLUSION: This study confirmed the prognostic value of hypoxia PET in LASCCHN for LC. Outcome after hypoxia DE appears promising and may support the concept of DE. Slow accrual and premature closure may partly be due to a high complexity of the study setup which needs to be considered for future multicenter trials.

Central Insulin Modulates Dopamine Signaling in the Human Striatum.

OBJECTIVE: Activity in the dopaminergic pathways of the brain is highly sensitive to body weight and metabolic states. Animal studies show that dopamine neurons are important targets for the metabolic hormone insulin with abolished effects in the insulin-resistant state, leading to increases in body weight and food intake. In humans, the influence of central acting insulin on dopamine and effects of their interplay are still elusive. RESEARCH DESIGN AND METHODS: We investigated whether central administered insulin influences dopaminergic activity in striatal regions and whole-brain neural activity. Using a positron emission tomography (PET)/magnetic resonance imaging (MRI) hybrid scanner, we simultaneously performed [11C]-raclopride-PET and resting-state functional MRI in 10 healthy normal-weight men after application of intranasal insulin or placebo on 2 separate days in a randomized, placebo-controlled, blinded, crossover trial. RESULTS: In response to central insulin compared with placebo administration, we observed greater [11C]-raclopride binding potential in the bilateral ventral and dorsal striatum. This suggests an insulin-induced reduction in synaptic dopamine levels. Resting-state striatal activity was lower 15 and 30 minutes after nasal insulin compared with placebo. Functional connectivity of the mesocorticolimbic circuitry associated with differences in dopamine levels: individuals with a stronger insulin-induced effect on dopamine levels showed a stronger increase in functional connectivity 45 minutes after intranasal insulin. CONCLUSIONS: This study indicates that central insulin modulates dopaminergic tone in the striatum, which may affect regional brain activity and connectivity. Our results deepen the understanding of the insulin-dopamine interaction and the complex network that underlies the regulation of whole-body metabolism.

Retrospective analysis of recurrence patterns and clinical outcome of grade II meningiomas following postoperative radiotherapy.

BACKGROUND: Atypical meningiomas exhibit a high tendency for tumor recurrence even after multimodal therapy. Information regarding recurrence patterns after additive radiotherapy is scarce but could improve radiotherapy planning and therapy decision. We conducted an analysis of recurrence patterns with regard to target volumes and dose coverage assessing target volume definition and postulated areas of tumor re-growth origin. Prognostic factors contributing to relapse were evaluated. METHODS: The clinical outcome of patients who had completed additive, somatostatin receptor (SSTR)-PET/CT-based fractionated intensity-modulated radiotherapy for atypical meningioma between 2007 and 2017 was analyzed. In case of tumor recurrence/progression, treatment planning was evaluated for coverage of the initial target volumes and the recurrent tumor tissue. We proposed a model evaluating the dose distribution in postulated areas of tumor re-growth origin. The median of proliferation marker MIB-1 was assessed as a prognostic factor for local progression and new distant tumor lesions. RESULTS: Data from 31 patients who had received adjuvant (n = 11) or salvage radiotherapy (n = 20) were evaluated. Prescribed dose ranged from 54.0 to 60.0 Gy. Local control at five years was 67.9%. Analysis of treatment plans of the eight patients experiencing local failure proved sufficient extent of target volumes and coverage of the prescribed dose of at least 50.0 Gy as determined by mean dose, D98, D2, and equivalent uniform dose (EUD) of all initial target volumes, postulated growth-areas, and areas of recurrent tumor tissue. In all cases, local failure occurred in high-dose volumes. Tumors with a MIB-1 expression above the median (8%) showed a higher tendency for re-growth. CONCLUSIONS: The model showed adequate target volume and relative dose distribution but absolute dose appears lower in recurrent tumors without reaching statistical significance. This might provide a rationale for dose escalation studies. Biological factors such as MIB-1 might aid patients' stratification for dose escalation.

Abnormal Regional and Global Connectivity Measures in Subjective Cognitive Decline Depending on Cerebral Amyloid Status.

BACKGROUND: Amyloid-ß accumulation was found to alter precuneus-based functional connectivity (FC) in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia, but its impact is less clear in subjective cognitive decline (SCD), which in combination with AD pathologic change is theorized to correspond to stage 2 of the Alzheimer's continuum in the 2018 NIA-AA research framework. OBJECTIVE: This study addresses how amyloid pathology relates to resting-state fMRI FC in SCD, especially focusing on the precuneus. METHODS: From the DELCODE cohort, two groups of 24 age- and gender-matched amyloid-positive (SCDAß+) and amyloidnegative SCD (SCDß-) patients were selected according to visual [18F]-Florbetaben (FBB) PET readings, and studied with resting-state fMRI. Local (regional homogeneity [ReHo], fractional amplitude of low-frequency fluctuations [fALFF]) and global (degree centrality [DC], precuneus seed-based FC) measures were compared between groups. Follow-up correlation analyses probed relationships of group differences with global and precuneal amyloid load, as measured by FBB standard uptake value ratios (SUVR=⫖FBB). RESULTS: ReHo was significantly higher (voxel-wise p < 0.01, cluster-level p < 0.05) in the bilateral precuneus for SCDAß+patients, whereas fALFF was not altered between groups. Relatively higher precuneus-based FC with occipital areas (but no altered DC) was observed in SCDAß+ patients. In this latter cluster, precuneus-occipital FC correlated positively with global (SCDAß+) and precuneus SUVRFBB (both groups). CONCLUSION: While partial confounding influences due to a higher APOE ε4 carrier ratio among SCDAß+ patients cannot be excluded, exploratory results indicate functional alterations in the precuneus hub region that were related to amyloid-ß load, highlighting incipient pathology in stage 2 of the AD continuum.

Independent brain 18F-FDG PET attenuation correction using a deep learning approach with Generative Adversarial Networks.

OBJECTIVE: Attenuation correction (AC) of positron emission tomography (PET) data poses a challenge when no transmission data or computed tomography (CT) data are available, e.g. in stand alone PET scanners or PET/magnetic resonance imaging (MRI). In these cases, external imaging data or morphological imaging data are normally used for the generation of attenuation maps. Newly introduced machine learning methods however may allow for direct estimation of attenuation maps from non attenuation-corrected PET data (PETNAC). Our purpose was thus to establish and evaluate a method for independent AC of brain fluorine-18-fluorodeoxyglucose (18F-FDG) PET images only based on PETNAC using Generative Adversarial Networks (GAN). SUBJECTS AND METHODS: After training of the deep learning GAN framework on a paired training dataset of PETNAC and the corresponding CT images of the head from 50 patients, pseudo-CT images were generated from PETNAC of 40 validation patients, of which 20 were used for technical validation and 20 stemming from patients with CNS disorders were used for clinical validation. Pseudo-CT was used for subsequent AC of these validation data sets resulting in independently attenuation-corrected PET data. RESULTS: Visual inspection revealed a high degree of resemblance of generated pseudo-CT images compared to the acquired CT images in all validation data sets, with minor differences in individual anatomical details. Quantitative analyses revealed minimal underestimation below 5% of standardized uptake value (SUV) in all brain regions in independently attenuation-corrected PET data compared to the reference PET images. Color-coded error maps showed no regional bias and only minimal average errors around ±0%. Using independently attenuation-corrected PET data, no differences in image-based diagnoses were observed in 20 patients with neurological disorders compared to the reference PET images. CONCLUSION: Independent AC of brain 18F-FDG PET is feasible with high accuracy using the proposed, easy to implement deep learning framework. Further evaluation in clinical cohorts will be necessary to assess the clinical performance of this method.

Controls-based denoising, a new approach for medical image analysis, improves prediction of conversion to Alzheimer's disease with FDG-PET.

OBJECTIVE: The pattern expression score (PES), i.e., the degree to which a pathology-related pattern is present, is frequently used in FDG-brain-PET analysis and has been shown to be a powerful predictor of conversion to Alzheimer's disease (AD) in mild cognitive impairment (MCI). Since, inevitably, the PES is affected by non-pathological variability, our aim was to improve classification with the simple, yet novel approach to identify patterns of non-pathological variance in a separate control sample using principal component analysis and removing them from patient data (controls-based denoising, CODE) before calculating the PES. METHODS: Multi-center FDG-PET from 220 MCI patients (64 non-converter, follow-up ≥ 4 years; 156 AD converter, time-to-conversion ≤ 4 years) were obtained from the ADNI database. Patterns of non-pathological variance were determined from 262 healthy controls. An AD pattern was calculated from AD patients and controls. We predicted AD conversion based on PES only and on PES combined with neuropsychological features and ApoE4 genotype. We compared classification performance achieved with and without CODE and with a standard machine learning approach (support vector machine). RESULTS: Our model predicts that CODE improves the signal-to-noise ratio of AD-PES by a factor of 1.5. PES-based prediction of AD conversion improved from AUC 0.80 to 0.88 (p= 0.001, DeLong's method), sensitivity 69 to 83%, specificity 81% to 88% and Matthews correlation coefficient (MCC) 0.45 to 0.66. Best classification (0.93 AUC) was obtained when combining the denoised PES with clinical features. CONCLUSIONS: CODE, applied in its basic form, significantly improved prediction of conversion based on PES. The achieved classification performance was higher than with a standard machine learning algorithm, which was trained on patients, explainable by the fact that CODE used additional information (large sample of healthy controls). We conclude that the proposed, novel method is a powerful tool for improving medical image analysis that offers a wide spectrum of biomedical applications, even beyond image analysis.

Automated Definition of Skeletal Disease Burden in Metastatic Prostate Carcinoma: A 3D Analysis of SPECT/CT Images.

To meet the current need for skeletal tumor-load estimation in castration-resistant prostate cancer (CRPC), we developed a novel approach based on adaptive bone segmentation. In this study, we compared the program output with existing estimates and with the radiological outcome. Seventy-six whole-body single-photon emission computed tomographies/x-ray computed tomography with 3,3-diphosphono-1,2-propanedicarboxylic acid from mCRPC patients were analyzed. The software identified the whole skeletal volume (SVol) and classified the voxels metastases (MVol) or normal bone (BVol). SVol was compared with the estimation of a commercial software. MVol was compared with manual assessment and with prostate specific antigen (PSA) levels. Counts/voxel were extracted from MVol and BVol. After six cycles of 223RaCl2-therapy every patient was re-evaluated as having progressive disease (PD), stable disease (SD), or a partial response (PR). SVol correlated with that of the commercial software (R = 0.99, p < 0.001). MVol correlated with the manually-counted lesions (R = 0.61, p < 0.001) and PSA (R = 0.46, p < 0.01). PD had a lower counts/voxel in MVol than PR/SD (715 ± 190 vs. 975 ± 215 and 1058 ± 255, p < 0.05 and p < 0.01) and BVol (PD 275 ± 60, PR 515 ± 188 and SD 528 ± 162 counts/voxel, p < 0.001). Segmentation-based tumor load correlated with radiological/laboratory indices. Uptake was linked with the clinical outcome, suggesting that metastases in PD patients have a lower affinity for bone-seeking radionuclides and might benefit less from bone-targeted radioisotope therapies.

Prospective Evaluation of a Tumor Control Probability Model Based on Dynamic 18F-FMISO PET for Head and Neck Cancer Radiotherapy.

Our purpose was to evaluate an imaging parameter-response relationship between the extent of tumor hypoxia quantified by dynamic 18F-fluoromisonidazole (18F-FMISO) PET/CT and the risk of relapse after radiotherapy in patients with head and neck cancer. Methods: Before a prospective cohort of 25 head and neck cancer patients started radiotherapy, they were examined with dynamic 18F-FMISO PET/CT 0-240 min after tracer injection. 18F-FMISO image parameters, including a hypoxia metric, MFMISO, derived from pharmacokinetic modeling of dynamic 18F-FMISO and maximum tumor-to-muscle ratio (TMRmax) at 4 h after injection, gross tumor volume (GTV), relative hypoxic volume based on MFMISO, and a logistic regression model combining GTV and TMRmax, were assessed and compared with a previous training cohort (n = 15). Dynamic 18F-FMISO was used to validate a tumor control probability model based on MFMISO The prognostic potential with respect to local control of all potential parameters was validated using the concordance index for univariate Cox regression models determined from the training cohort, in addition to Kaplan-Meier analysis including the log-rank test. Results: The tumor control probability model was confirmed, indicating that dynamic 18F-FMISO allows stratification of patients into different risk groups according to radiotherapy outcome. In this study, MFMISO was the only parameter that was confirmed as prognostic in the independent validation cohort (concordance index, 0.71; P = 0.004). All other investigated parameters, such as TMRmax, GTV, relative hypoxic volume, and the combination of GTV and TMRmax, were not able to stratify patient groups according to outcome in this validation cohort (P = not statistically significant). Conclusion: In this study, the relationship between MFMISO and the risk of relapse was prospectively validated. The data support further evaluation and external validation of dynamic 18F-FMISO PET/CT as a promising method for patient stratification and hypoxia-based radiotherapy personalization, including dose painting.

The movement disorder spectrum of SCA21 (ATX-TMEM240): 3 novel families and systematic review of the literature.

Spinocerebellar ataxia type 21 (SCA21/ATX-TMEM240) was recently found to be caused by mutations in TMEM240, with still limited knowledge on the phenotypic spectrum and disease course. Here we present five subjects from three novel SCA21 families from different parts of the world (including a novel c.196G > A, p.G66R TMEM240 variant from Colombia), demonstrating that, in addition to cerebellar ataxia, not only hypokinetic features (hypomimia, bradykinesia), but also hyperkinetic movement disorders (poly-mini-myoclonus, proximal myoclonus) are a recurrent part of the phenotypic spectrum of SCA21. Presenting first prospective longitudinal data, our results provide examples of two different disease trajectories: while it was inherently progressive in adult-onset cases, a dramatically improving trajectory was observed in an infantile-onset case. A systematic review of all previously reported SCA21 patients (n = 42) demonstrates that SCA21 is a relatively early-onset SCA (median onset age 18 years; range 1-61 years) with frequent non-cerebellar involvement, including hyporeflexia (69%), bradykinesia (65%), slow saccades (38%) and pyramidal signs (17%). Our results characterize SCA21 as a multisystem disorder with substantial extra-cerebellar involvement, including a wide spectrum of hypo- as well as hyperkinetic movement disorders as well as damage to the midbrain, corticospinal tract and peripheral nerves. However, in contrast to the current perspective on SCA21 disease, cognitive impairment is not an obligatory feature of the disease. The disease course is inherently progressive in adult-onset subjects, but might also be characterized by improvement in infantile-onset cases. These findings have important consequences of the work-up and counseling of SCA21/ATX-TMEM240 patients.

Practice-based evidence for the clinical benefit of PET/CT-results of the first oncologic PET/CT registry in Germany.

PURPOSE: The purpose of this study was to evaluate the impact of PET/CT on clinical management of cancer patients based on a prospective data registry. The study was developed to inform consultations with public health insurances on PET/CT coverage. METHODS: We evaluated a prospective patient cohort having a clinically indicated PET/CT at a single German University Center from April 2013 to August 2016. The registry collected questionnaire data from requesting physicians on intended patient management before and after PET/CT. A total of 4,504 patients with 5,939 PET/CT examinations were enrolled in the registry, resulting in evaluable data from 3,724 patients receiving 4,754 scans. The impact of PET/CT on patient management was assessed across 22 tumor types, for different indications (diagnosis, staging, suspected recurrence) and different categories of management including treatment (curative or palliative) and non-treatment (watchful waiting, additional imaging, invasive tests). RESULTS: The most frequent PET/CT indication was tumor staging (59.7%). Melanoma, lung cancer, lymphoma, neuroendocrine tumor and prostate cancer accounted for 70% of cases. Overall, the use of PET/CT resulted in a 37.1% change of clinical management (95% CI, 35.7-38.5), most frequently (30.6%) from an intended non-treatment strategy before PET/CT to active treatment after PET/CT. The frequency of changes ranged from 28.3% for head and neck cancers up to 46.0% for melanomas. The impact of PET/CT was greatest in reducing demands for additional imaging which decreased from 66.1% before PET/CT to 6.1% after PET/CT. Pre-PET/CT planned invasive tests could be avoided in 72.7% of cases. The treatment goal changed after PET/CT in 21.7% of cases, in twice as many cases from curative to palliative therapy than vice versa. CONCLUSIONS: The data of this large prospective registry confirm that physicians often change their intended management on the basis of PET/CT by initiating treatment and reducing additional imaging as well as invasive tests. This applies to various cancer types and indications.

Smoking moderates association of 5-HTTLPR and in vivo availability of serotonin transporters.

Although preclinical studies clearly indicate an effect of 5-HTTLPR genotype on 5-HT transporter (5-HTT) expression, studies in humans provided inconclusive results, hypothetically due to environmental factors and differences in individual behavior. For example, nicotine and other constituents of tobacco smoke elevate serotonin (5-HT) levels in the brain and may thereby cause homeostatic adaptations in 5-HTT availability that moderate effects of 5-HTTLPR genotype. To test whether 5-HTT availability in the midbrain is affected by smoking status and 5-HTTLPR genotype, we pooled data from prior studies on in vivo 5-HTT availability (BPND) measured with positron emission tomography (PET) and [11C]DASB. In total, we reanalyzed 5-HTT availability in 116 subjects using ANCOVA statistics. ROI analysis revealed that current smokers and non-smokers do not differ in midbrain BPND. Interestingly, smoking status significantly interacted with 5-HTTLPR genotype: active smoking was associated with reduced 5-HTT availability only in LL subjects but not in carriers of the S-allele. From the perspective of genotype effects, non-smokers showed the expected association with 5-HTTLPR, i.e. higher 5-HTT availability in LL subjects compared to carriers of the S-allele, whereas this pattern was actually reversed for active smokers. Our study indicates that smoking status moderates the association of 5-HTTLPR genotype and 5-HTT expression, which may help to explain inconsistent findings in previous studies. Regarding the mechanism, we suggest that smoking may induce epigenetic processes such as methylation of SLC6A4, which can differ depending on its genetic constitution.

Hypermetabolism in the cerebellum and brainstem and cortical hypometabolism are independently associated with cognitive impairment in Parkinson's disease.

PURPOSE: Cognitive impairment (CI) in Parkinson's disease (PD) is associated with a widespread reduction in cortical glucose metabolism and relative increases in the cerebellum and brainstem as measured using 18F-fluorodesoxyglucose (FDG) PET. We separately analysed CI-related hypermetabolism and hypometabolism in comparison with neuropsychological test performance and investigated whether increased FDG uptake is a true feature of the disease or a normalization effect. METHODS: The study included 29 subjects (12 patients with PD, 10 patients with PD dementia and 7 healthy controls") who underwent FDG PET and comprehensive neuropsychological testing. Test performance across various cognitive domains was summarized in a cognitive staging score. Metabolic indices reflecting associated changes in regional cerebral glucose metabolism (rCGM) were calculated: index(-) for CI-related hypometabolism, and index(+) for CI-related hypermetabolism. We tested whether index(+) offered additional value in predicting the severity of CI in multiple regression analysis. RESULTS: At higher stages of CI, increased rCGM was found in the posterior cerebellar vermis and pons, associated with impaired attention, executive function and memory. Reduced rCGM was found in various cortical regions in agreement with the literature. In multiple regression analysis, both indices independently predicted the severity of CI with a whole-model R2 of 0.68 (index(-), p = 0.0006; index(+), p = 0.013), confirmed by alternative analyses combining different reference tissues in the multiple regression. CONCLUSION: We found CI-related hypermetabolism in cerebellar regions that are known to be involved in several cognitive functions and in the pons. These alterations may represent compensatory activation of cognitive networks including cerebropontocerebellar tracts.

Simultaneous multislice diffusion-weighted imaging in whole-body positron emission tomography/magnetic resonance imaging for multiparametric examination in oncological patients.

OBJECTIVES: The aim of this study was to compare the diagnostic performance of simultaneous multislice diffusion-weighted imaging (DWI-SMS) with that of standard DWI (DWI-STD) in whole-body 3-T PET/MRI examination protocols in oncological patients. METHODS: In a phantom study, we evaluated the apparent diffusion coefficients (ADC) from the two techniques. In ten volunteers, we assessed ADC values in different organs. In 20 oncological patients, we evaluated subjective image quality (Likert scale, 5 indicating excellent) and artefacts in different body regions. We also rated the conspicuity and acquired the ADC values of PET-positive tumorous lesions. RESULTS: The scan time for the whole-body DWI-SMS examinations was 40% shorter than the scan time for the DWI-STD examinations (84 s vs. 140 s per table position). The phantom and volunteer studies showed lower ADC values from DWI-SMS in the liver and muscle (psoas muscle 1.4 vs. 1.3). In patients, DWI-SMS provided poorer subjective image quality in the thoracoabdominal region (3.0 vs. 3.8, p = 0.02) and overall more artefacts (138 vs. 105). No significant differences regarding conspicuity and ADC values of lesions were found. CONCLUSIONS: DWI-SMS seems to provide reliable conspicuity and ADC values of tumorous lesions similar to those provided by DWI-STD. Therefore, although providing poorer image quality in certain regions, DWI-SMS can clearly reduce PET/MRI scan times in oncological patients. KEY POINTS: • DWI-SMS can reduce PET/MRI scan times in oncological patients. • DWI-SMS provides reliable ADC values and good lesion conspicuity similar to those provided by DWI-STD. • DWI-SMS may provide poorer image quality in regions with low signal.

Pancreatic Ductal Adenocarcinoma With High Radiotracer Uptake in 68Ga-Prostate-Specific Membrane Antigen PET/CT.

Prostate-specific membrane antigen imaging with PET/CT is increasingly used in prostate cancer and was shown to have a high diagnostic performance. We report a clinical case of a 67-year-old man with previous history of operated prostate cancer and increasing prostate-specific antigen blood level. Ga-HBED-CC prostate-specific membrane antigen PET/CT imaging was indicated for the assessment of local recurrence and lymph node metastases of prostate cancer. In addition, a soft tissue mass in the body of the pancreas with high radiotracer uptake was detected. Histopathology confirmed a pancreatic ductal adenocarcinoma.