Asymmetry of thalamic hypometabolism on FDG-PET/CT in neurofibromatosis type 1: Association with peripheral tumor burden.

BACKGROUND AND PURPOSE: Thalamic hypometabolism is a consistent finding in brain PET with F-18 fluorodeoxyglucose (FDG) in patients with neurofibromatosis type 1 (NF1). However, the pathophysiology of this metabolic alteration is unknown. We hypothesized that it might be secondary to disturbance of peripheral input to the thalamus by NF1-characteristic peripheral nerve sheath tumors (PNSTs). To test this hypothesis, we investigated the relationship between thalamic FDG uptake and the number, volume, and localization of PNSTs. METHODS: This retrospective study included 22 adult NF1 patients (41% women, 36.2 ± 13.0 years) referred to whole-body FDG-PET/contrast-enhanced CT for suspected malignant transformation of PNSTs and 22 sex- and age-matched controls. Brain FDG uptake was scaled voxelwise to the individual median uptake in cerebellar gray matter. Bilateral mean and left-right asymmetry of thalamic FDG uptake were determined using a left-right symmetric anatomical thalamus mask. PNSTs were manually segmented in contrast-enhanced CT. RESULTS: Thalamic FDG uptake was reduced in NF1 patients by 2.0 standard deviations (p < .0005) compared to controls. Left-right asymmetry was increased by 1.3 standard deviations (p = .013). Thalamic hypometabolism was higher in NF1 patients with ≥3 PNSTs than in patients with ≤2 PNSTs (2.6 vs. 1.6 standard deviations, p = .032). The impact of the occurrence of paraspinal/paravertebral PNSTs and of the mean PNST volume on thalamic FDG uptake did not reach statistical significance (p = .098 and p = .189). Left-right asymmetry of thalamic FDG uptake was not associated with left-right asymmetry of PNST burden (p = .658). CONCLUSIONS: This study provides first evidence of left-right asymmetry of thalamic hypometabolism in NF1 and that it might be mediated by NF1-associated peripheral tumors.

Automatic segmentation of the thalamus using a massively trained 3D convolutional neural network: higher sensitivity for the detection of reduced thalamus volume by improved inter-scanner stability.

OBJECTIVES: To develop an automatic method for accurate and robust thalamus segmentation in T1w-MRI for widespread clinical use without the need for strict harmonization of acquisition protocols and/or scanner-specific normal databases. METHODS: A three-dimensional convolutional neural network (3D-CNN) was trained on 1975 T1w volumes from 170 MRI scanners using thalamus masks generated with FSL-FIRST as ground truth. Accuracy was evaluated with 18 manually labeled expert masks. Intra- and inter-scanner test-retest stability were assessed with 477 T1w volumes of a single healthy subject scanned on 123 MRI scanners. The sensitivity of 3D-CNN-based volume estimates for the detection of thalamus atrophy was tested with 127 multiple sclerosis (MS) patients and a normal database comprising 4872 T1w volumes from 160 scanners. The 3D-CNN was compared with a publicly available 2D-CNN (FastSurfer) and FSL. RESULTS: The Dice similarity coefficient of the automatic thalamus segmentation with manual expert delineation was similar for all tested methods (3D-CNN and FastSurfer 0.86 ± 0.02, FSL 0.87 ± 0.02). The standard deviation of the single healthy subject's thalamus volume estimates was lowest with 3D-CNN for repeat scans on the same MRI scanner (0.08 mL, FastSurfer 0.09 mL, FSL 0.15 mL) and for repeat scans on different scanners (0.28 mL, FastSurfer 0.62 mL, FSL 0.63 mL). The proportion of MS patients with significantly reduced thalamus volume was highest for 3D-CNN (24%, FastSurfer 16%, FSL 11%). CONCLUSION: The novel 3D-CNN allows accurate thalamus segmentation, similar to state-of-the-art methods, with considerably improved robustness with respect to scanner-related variability of image characteristics. This might result in higher sensitivity for the detection of disease-related thalamus atrophy. KEY POINTS: • A three-dimensional convolutional neural network was trained for automatic segmentation of the thalamus with a heterogeneous sample of T1w-MRI from 1975 patients scanned on 170 different scanners. • The network provided high accuracy for thalamus segmentation with manual segmentation by experts as ground truth. • Inter-scanner variability of thalamus volume estimates across different MRI scanners was reduced by more than 50%, resulting in increased sensitivity for the detection of thalamus atrophy.

Effects of spermidine supplementation on cognition and biomarkers in older adults with subjective cognitive decline (SmartAge)-study protocol for a randomized controlled trial.

BACKGROUND: Given the global increase in the aging population and age-related diseases, the promotion of healthy aging is one of the most crucial public health issues. This trial aims to contribute to the establishment of effective approaches to promote cognitive and brain health in older individuals with subjective cognitive decline (SCD). Presence of SCD is known to increase the risk of objective cognitive decline and progression to dementia due to Alzheimer's disease. Therefore, it is our primary goal to determine whether spermidine supplementation has a positive impact on memory performance in this at-risk group, as compared with placebo. The secondary goal is to examine the effects of spermidine intake on other neuropsychological, behavioral, and physiological parameters. METHODS: The SmartAge trial is a monocentric, randomized, double-blind, placebo-controlled phase IIb trial. The study will investigate 12 months of intervention with spermidine-based nutritional supplementation (target intervention) compared with 12 months of placebo intake (control intervention). We plan to recruit 100 cognitively normal older individuals with SCD from memory clinics, neurologists and general practitioners in private practice, and the general population. Participants will be allocated to one of the two study arms using blockwise randomization stratified by age and sex with a 1:1 allocation ratio. The primary outcome is the change in memory performance between baseline and post-intervention visits (12 months after baseline). Secondary outcomes include the change in memory performance from baseline to follow-up assessment (18 months after baseline), as well as changes in neurocognitive, behavioral, and physiological parameters (including blood and neuroimaging biomarkers), assessed at baseline and post-intervention. DISCUSSION: The SmartAge trial aims to provide evidence of the impact of spermidine supplementation on memory performance in older individuals with SCD. In addition, we will identify possible neurophysiological mechanisms of action underlying the anticipated cognitive benefits. Overall, this trial will contribute to the establishment of nutrition intervention in the prevention of Alzheimer's disease. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03094546 . Registered 29 March 2017-retrospectively registered. PROTOCOL VERSION: Based on EA1/250/16 version 1.5.

Cerebral glucose metabolism in adults with neurofibromatosis type 1.

Previous studies with positron emission tomography (PET) and the glucose analog F-18-fluorodeoxyglucose (FDG) in patients with neurofibromatosis type 1 (NF1) suggest reduced cerebral glucose metabolism in NF1 specifically in the thalamus. The latter is distinguished by extensive neural circuitry connections which makes thalamic hypoactivity in NF1 an interesting finding. Yet it is not very well confirmed, since previous studies were limited by small sample size and/or poorly matched control groups. Primary aim of the present study therefore was to compare brain FDG PET between a large sample of NF1 patients and a well-matched control group. Secondary aim was to test for an NF1-associated FDG effect in the amygdala, as increased blood flow in the amygdala has recently been detected in a mouse model of NF1. Fifty adult NF1 patients and 50 gender- and age-matched control subjects were included retrospectively. Voxel-wise comparison of brain FDG uptake was performed using the statistical parametric mapping (SPM8). Additional region-of-interest (ROI) analysis was performed using standard ROI templates. Voxel-based testing revealed a single 11.2 ml cluster of reduced FDG uptake in the thalamus of NF1 patients. There was no further significant cluster throughout the whole brain including the amygdala, neither hypo nor hyper. ROI-analysis confirmed reduction of thalamic FDG uptake in the NF1 group (p<0.0005) with a magnitude of 7.6%. In conclusion, adults with NF1 show reduced brain activity specifically in thalamus. There is no indication of abnormal brain activity in the amygdala in humans with NF1.

Prefrontal and Striatal Glutamate Differently Relate to Striatal Dopamine: Potential Regulatory Mechanisms of Striatal Presynaptic Dopamine Function?

Theoretical and animal work has proposed that prefrontal cortex (PFC) glutamate inhibits dopaminergic inputs to the ventral striatum (VS) indirectly, whereas direct VS glutamatergic afferents have been suggested to enhance dopaminergic inputs to the VS. In the present study, we aimed to investigate relationships of glutamate and dopamine measures in prefrontostriatal circuitries of healthy humans. We hypothesized that PFC and VS glutamate, as well as their balance, are differently associated with VS dopamine. Glutamate concentrations in the left lateral PFC and left striatum were assessed using 3-Tesla proton magnetic resonance spectroscopy. Striatal presynaptic dopamine synthesis capacity was measured by fluorine-18-l-dihydroxyphenylalanine (F-18-FDOPA) positron emission tomography. First, a negative relationship was observed between glutamate concentrations in lateral PFC and VS dopamine synthesis capacity (n = 28). Second, a positive relationship was revealed between striatal glutamate and VS dopamine synthesis capacity (n = 26). Additionally, the intraindividual difference between PFC and striatal glutamate concentrations correlated negatively with VS dopamine synthesis capacity (n = 24). The present results indicate an involvement of a balance in PFC and striatal glutamate in the regulation of VS dopamine synthesis capacity. This notion points toward a potential mechanism how VS presynaptic dopamine levels are kept in a fine-tuned range. A disruption of this mechanism may account for alterations in striatal dopamine turnover as observed in mental diseases (e.g., in schizophrenia). SIGNIFICANCE STATEMENT: The present work demonstrates complementary relationships between prefrontal and striatal glutamate and ventral striatal presynaptic dopamine using human imaging measures: a negative correlation between prefrontal glutamate and presynaptic dopamine and a positive relationship between striatal glutamate and presynaptic dopamine are revealed. The results may reflect a regulatory role of prefrontal and striatal glutamate for ventral striatal presynaptic dopamine levels. Such glutamate-dopamine relationships improve our understanding of neurochemical interactions in prefrontostriatal circuits and have implications for the neurobiology of mental disease.

Cost comparison of 111In-DTPA-octreotide scintigraphy and 68Ga-DOTATOC PET/CT for staging enteropancreatic neuroendocrine tumours.

PURPOSE: Although somatostatin receptor positron emission tomography (PET)/CT is gaining increasing popularity and has shown its diagnostic superiority in several studies, (111)In-diethylenetriaminepentaacetic acid (DTPA)-octreotide is still the current standard for diagnosis of neuroendocrine tumours (NET). The aim of this study was to compare the costs for the two diagnostic tests and the respective consequential costs. METHODS: From January 2009 to July 2009, 51 consecutive patients with enteropancreatic NET who underwent contrast-enhanced (68)Ga-DOTATOC PET/CT (n = 29) or (111)In-DTPA-octreotide (mean 3 whole-body scans plus 1.6 low-dose single photon emission computed tomography/CT; n = 22) were included. For cost analysis, direct costs (equipment) and variable costs (material, labour) per examination were calculated. Additionally required CT and/or MRI examinations within the staging process were assessed as consequential costs. An additional deterministic sensitivity analysis was performed. RESULTS: A (68)Ga-DOTATOC PET/CT examination yielded total costs (equipment, personnel and material costs) of 548 euro. On the other hand, an (111)In-DTPA-octreotide examination resulted in 827 euro total costs. Costs for equipment and material had a share of 460 euro/720 euro for (68)Ga-DOTATOC/(111)In-DTPA-octreotide and labour costs of 89 euro/106 euro. With (68)Ga-DOTATOC additional MRI had to be performed in 7% of the patients resulting in a mean of 20 euro for supplementary imaging per patient; 82% of patients with (111)In-DTPA-octreotide needed additional MRI and/or CT resulting in mean additional costs of 161 euro per patient. CONCLUSION: (68)Ga-DOTATOC PET/CT was considerably cheaper than (111)In-DTPA-octreotide with respect to both material and personnel costs. Furthermore, by using (68)Ga-DOTATOC PET/CT considerably fewer additional examinations were needed reducing the consequential costs significantly.

Reduced thalamic 18F-flurodeoxyglucose retention in adults with neurofibromatosis type 1.

OBJECTIVE: Neurofibromatosis type1 (NF1) is associated with cognitive and motor deficits whose pathogenesis is not well understood. 18F-Flurodeoxyglucose positron emission tomography (FDG PET) might be used to investigate putative functional correlates in the brain. METHODS: Whole-body FDG PET including the brain had been performed in 29 NF1 patients suspected for malignant peripheral nerve sheath tumours (20 females, nine males, age 31.2+/-11.8 years). Twenty-nine age-matched and sex-matched subjects without evidence of neurological/psychiatric disease in whom FDG PET had been performed for NF1-unrelated oncological indication served as controls. Individual brain FDG retention images were stereotactically normalized and scaled to a common median retention value within the brain. Scaled FDG retention was compared between the NF1 group and the control group on a voxel-by-voxel base using ANCOVA in SPM2 with the FDG uptake period as covariate. The corrected significance level alpha=0.05 was used. Voxel-based analysis was complemented by volume of interest (VOI)-based analysis using predefined standard VOIs. RESULTS: The voxel-based group comparison revealed a significant reduction of scaled FDG retention in the thalamus of the NF1 subjects within a cluster of 11.6 ml. There were no further significant effects, neither hypo-retention nor hyper-retention. Reduction of relative FDG retention in the thalamus in the NF1 subjects was confirmed by VOI analysis. The magnitude of the reduction was about 8%. CONCLUSIONS: The thalamus appears to be affected in adults with NF1. The observed magnitude of the reduction of scaled thalamic FDG retention in adults is smaller than previously reported in children. This may be consistent with a stabilization of the disease process with age.

Limitations of bi-linear regression analysis for the determination of receptor occupancy with positron emission tomography.

BACKGROUND AND OBJECTIVES: Linear/multilinear regression methods are widely used in quantitative neuroreceptor positron emission tomography. A reference tissue method based on a bi-linear operational equation, the bi-linear reference tissue method, has been introduced in order to overcome the need for arterial blood sampling. The aim of the present paper was to investigate the sensitivity of the bi-linear reference tissue method to statistical noise, with special regard to the assessment of receptor occupancy. In addition, improvement of the bi-linear reference tissue method by regularization using physiological constraints was evaluated. METHODS: Application of the bi-linear method to dynamic positron emission tomography using the serotonin transporter ligand C-(+)McN5652 was considered. Investigations were performed by computer simulations and analysis of 29 patient studies. RESULTS: The equilibrium specific-to-non-specific partition coefficient V"3 was significantly underestimated by the bi-linear reference tissue method. At realistic noise levels the extent of the underestimation ranged from 25% to 75% for partition coefficients ranging from 0.3 to 0.3, respectively. This caused a 15-60% underestimation of changes in receptor occupancy after simulated intervention. The noise dependence of the bias was confirmed in the patient studies. Regularization significantly reduced the underestimation of the occupancy. CONCLUSIONS: When receptor status or noise level vary substantially, as in receptor occupancy studies, the bias of the bi-linear reference tissue method should be taken into account.