Amyloid and SCD jointly predict cognitive decline across Chinese and German cohorts.

INTRODUCTION: Subjective cognitive decline (SCD) in amyloid-positive (Aß+) individuals was proposed as a clinical indicator of Stage 2 in the Alzheimer's disease (AD) continuum, but this requires further validation across cultures, measures, and recruitment strategies. METHODS: Eight hundred twenty-one participants from SILCODE and DELCODE cohorts, including normal controls (NC) and individuals with SCD recruited from the community or from memory clinics, underwent neuropsychological assessments over up to 6 years. Amyloid positivity was derived from positron emission tomography or plasma biomarkers. Global cognitive change was analyzed using linear mixed-effects models. RESULTS: In the combined and stratified cohorts, Aß+ participants with SCD showed steeper cognitive decline or diminished practice effects compared with NC or Aß- participants with SCD. These findings were confirmed using different operationalizations of SCD and amyloid positivity, and across different SCD recruitment settings. DISCUSSION: Aß+ individuals with SCD in German and Chinese populations showed greater global cognitive decline and could be targeted for interventional trials. HIGHLIGHTS: SCD in amyloid-positive (Aß+) participants predicts a steeper cognitive decline. This finding does not rely on specific SCD or amyloid operationalization. This finding is not specific to SCD patients recruited from memory clinics. This finding is valid in both German and Chinese populations. Aß+ older adults with SCD could be a target population for interventional trials.

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.

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.

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.

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.

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.

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.

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.

No parkinsonism in SCA2 and SCA3 despite severe neurodegeneration of the dopaminergic substantia nigra.

See Klockgether (doi:10.1093/awv253) for a scientific commentary on this article.The spinocerebellar ataxias types 2 (SCA2) and 3 (SCA3) are autosomal dominantly inherited cerebellar ataxias which are caused by CAG trinucleotide repeat expansions in the coding regions of the disease-specific genes. Although previous post-mortem studies repeatedly revealed a consistent neurodegeneration of the dopaminergic substantia nigra in patients with SCA2 and with SCA3, parkinsonian motor features evolve only rarely. As the pathophysiological mechanism how SCA2 and SCA3 patients do not exhibit parkinsonism is still enigmatic, we performed a positron emission tomography and a post-mortem study of two independent cohorts of SCA2 and SCA3 patients with and without parkinsonian features. Positron emission tomography revealed a significant reduction of dopamine transporter levels in the striatum as well as largely unaffected postsynaptic striatal D2 receptors. In spite of this remarkable pathology in the motor mesostriatal pathway, only 4 of 19 SCA2 and SCA3 patients suffered from parkinsonism. The post-mortem investigation revealed, in addition to an extensive neuronal loss in the dopaminergic substantia nigra of all patients with spinocerebellar ataxia, a consistent affection of the thalamic ventral anterior and ventral lateral nuclei, the pallidum and the cholinergic pedunculopontine nucleus. With the exception of a single patient with SCA3 who suffered from parkinsonian motor features during his lifetime, the subthalamic nucleus underwent severe neuronal loss, which was clearly more severe in its motor territory than in its limbic or associative territories. Our observation that lesions of the motor territory of the subthalamic nucleus were consistently associated with the prevention of parkinsonism in our SCA2 and SCA3 patients matches the clinical experience that selective targeting of the motor territory of the subthalamic nucleus by focal lesions or deep brain stimulation can ameliorate parkinsonian motor features and is likely to counteract the manifestation of parkinsonism in SCA2 and SCA3 despite a severe neurodegeneration of the dopaminergic substantia nigra.

Simultaneous whole-body PET/MR imaging in comparison to PET/CT in pediatric oncology: initial results.

PURPOSE: To compare positron emission tomography (PET)/magnetic resonance (MR) imaging and PET/computed tomography (CT) for lesion detection and interpretation, quantification of fluorine 18 ((18)F) fluorodeoxyglucose (FDG) uptake, and accuracy of MR-based PET attenuation correction in pediatric patients with solid tumors. Materials and Methods This prospective study had local ethics committee and German Federal Institute for Drugs and Medical Devices approval. Written informed consent was obtained from all patients and legal guardians. Twenty whole-body (18)F-FDG PET/CT and (18)F-FDG PET/MR examinations were performed in 18 pediatric patients (median age, 14 years; range, 11-17 years). (18)F-FDG PET/CT and (18)F-FDG PET/MR data were acquired sequentially on the same day for all patients. PET standardized uptake values (SUVs) were quantified with volume of interest measurements in lesions and healthy tissues. MR-based PET attenuation correction was compared with CT-derived attenuation maps (µ-maps). Lesion detection was assessed with separate reading of PET/CT and PET/MR data. Estimates of radiation dose were derived from the applied doses of (18)F-FDG and CT protocol parameters. Descriptive statistical analyses were performed to report correlation coefficients and relative deviations for comparison of SUVs, rates of lesion detection, and percentage reductions in radiation dose. RESULTS: PET SUVs showed strong correlations between PET of PET/CT (PETCT) and PET of PET/MR (PETMR) (r > 0.85 for most tissues). Apart from drawbacks of MR-based PET attenuation correction in osseous structures and lungs, similar SUVs were found on PET images corrected with CT-based µ-maps (13.1% deviation of SUVs for bone marrow and <5% deviation for other tissues). Lesion detection rate with PET/MR imaging was equivalent to that with PET/CT (61 areas of focal uptake on PETMR images vs 62 areas on PETCT images). Advantages of PET/MR were observed especially in soft-tissue regions. Furthermore, PET/MR offered significant dose reduction (73%) compared with PET/CT. CONCLUSION: Pediatric oncologic PET/MR is technically feasible, showing satisfactory performance for PET quantification with SUVs similar to those of PET/CT. Compared with PET/CT, PET/MR demonstrates equivalent lesion detection rates while offering markedly reduced radiation exposure. Thus, PET/MR is a promising modality for the clinical work-up of pediatric malignancies. Online supplemental material is available for this article.

High apolipoprotein E in cerebrospinal fluid of patients with Lewy body disorders is associated with dementia.

Apolipoprotein E ε4 allele (APOE ε4) increases the apolipoprotein E (apoE) protein levels in Alzheimer's disease (AD) cerebrospinal fluid (CSF). Thus, we hypothesized that apoE levels were also associated with the APOE genotype, and amyloid-ß (Aß)-associated clinical, functional, and imaging parameters in patients with Lewy body-associated disorders (LBD). Indeed, similar to AD, patients with LBD displayed high CSF apoE levels (greatest in patients with dementia with LBD), and this was linked to APOE ε4. High CSF apoE protein correlated positively with CSF soluble amyloid precursor protein, total tau, and cortical and striatal Pittsburgh compound B retention; and correlated negatively with CSF Aß42, cognitive tests scores, and glucose uptake ratio in the temporal and parietal cortices. APOE ε4-triggered accumulation of apoE in CSF is related to Aß-associated clinical and functional imaging parameters in LBD. Accordingly, therapeutic strategies aimed at reducing apoE levels in the brain should be explored not only in AD but also in LBD, particularly when accompanied with dementia.

Correlation between [¹8F]FDG PET/CT and volume perfusion CT in primary tumours and mediastinal lymph nodes of non-small-cell lung cancer.

PURPOSE: The aim of this study was to investigate correlations between glucose metabolism as determined by [(18)F]FDG PET/CT and tumour perfusion as quantified by volume perfusion CT in primary tumours and mediastinal lymph nodes (MLN) of patients with non-small-cell lung cancer (NSCLC). METHODS: Enrolled in the study were 17 patients with NSCLC. [(18)F]FDG uptake was quantified in terms of SUVmax and SUVavg. Blood flow (BF), blood volume (BV) and flow extraction product (K(trans)) were determined as perfusion parameters. The correlations between the perfusion parameters and [(18)F]FDG uptake values were subsequently evaluated. RESULTS: For the primary tumours, no correlations were found between perfusion parameters and [(18)F]FDG uptake. In MLN, there were negative correlations between BF and SUVavg (r = -0.383), BV and SUVavg (r = -0.406), and BV and SUVmax (r = -0.377), but not between BF and SUVmax, K(trans) and SUVavg, or K(trans) and SUVmax. Additionally, in MLN with SUVmax >2.5 there were negative correlations between BF and SUVavg (r = -0.510), BV and SUVavg (r = -0.390), BF and SUVmax (r = -0.536), as well as BV and SUVmax (r = -0.346). CONCLUSION: Perfusion and glucose metabolism seemed to be uncoupled in large primary tumours, but an inverse correlation was observed in MLN. This information may help improve therapy planning and response evaluation.

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.

Fluorodeoxyglucose positron emission tomography in Richardson's syndrome and progressive supranuclear palsy-parkinsonism.

BACKGROUND: We hypothesized that postural instability and cognitive decline in patients with Richardson's syndrome could be a consequence of reduced thalamic and frontal metabolism. Severe Parkinsonian signs in patients with progressive supranuclear palsy-parkinsonism may be reflected by alterations in putaminal metabolism. METHODS: Eleven patients with Richardson's syndrome, 8 patients with progressive supranuclear palsy-parkinsonism, 12 with Parkinson's disease, and 10 controls underwent clinical assessment and fluorodeoxyglucose positron emission tomography (PET). RESULTS: Richardson's syndrome patients showed pronounced thalamic hypometabolism, and patients with progressive supranuclear palsy-parkinsonism pronounced putaminal hypometabolism, compared to all other investigated groups. The putamen/thalamus uptake ratio differentiated progressive supranuclear palsy-parkinsonism from Richardson's syndrome (area under the curve 5 0.86) and from Parkinson's disease (area under the curve 5 0.80) with acceptable accuracy. Frontal hypometabolism was predominantly found in Richardson's syndrome patients. CONCLUSIONS: Richardson's syndrome, progressive supranuclear palsy-parkinsonism and Parkinson's disease showed different metabolic patterns in fluorodeoxyglucose PET.

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.

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.

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.

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.

Cortical PIB binding in Lewy body disease is associated with Alzheimer-like characteristics.

About one fourth of Lewy body disease (LBD) patients show cortical beta-amyloid load, basically a hallmark of Alzheimer disease (AD). Using [11C]PIB-PET, we tested whether LBD patients with beta-amyloid burden differ from those without with respect to demographic, clinical, biochemical and genetic parameters. Thirty-five LBD subjects (9 patients with Lewy body dementia, DLB; 12 demented Parkinson patients, PDD; 14 non-demented PD, PDND) underwent [11C]PIB-PET, and were classified as either PIB(+) or PIB(-) according to cortical PIB uptake. PIB+ and PIB(-) patients were then compared according to demographic, clinical, biochemical and genetic parameters. None of the PDND, but four PDD and four DLB subjects were PIB+. In PIB+ subjects, ApoE4 prevalence was higher, CSF Abeta42 levels were lower and, among demented patients, PIB-binding was associated with a lower MMSE score. Motor symptoms were not associated with PIB binding. Thus, LBD patients with cortical beta-amyloid show characteristics usually observed in AD.