Relevance of 18F-DOPA visual and semi-quantitative PET metrics for the diagnostic of Parkinson disease in clinical practice: a machine learning-based inference study.

PURPOSE: To decipher the relevance of visual and semi-quantitative 6-fluoro-(18F)-L-DOPA (18F-DOPA) interpretation methods for the diagnostic of idiopathic Parkinson disease (IPD) in hybrid positron emission tomography (PET) and magnetic resonance imaging. MATERIAL AND METHODS: A total of 110 consecutive patients (48 IPD and 62 controls) with 11 months of median clinical follow-up (reference standard) were included. A composite visual assessment from five independent nuclear imaging readers, together with striatal standard uptake value (SUV) to occipital SUV ratio, striatal gradients and putamen asymmetry-based semi-quantitative PET metrics automatically extracted used to train machine learning models to classify IPD versus controls. Using a ratio of 70/30 for training and testing sets, respectively, five classification models-k-NN, LogRegression, support vector machine, random forest and gradient boosting-were trained by using 100 times repeated nested cross-validation procedures. From the best model on average, the contribution of PET parameters was deciphered using the Shapley additive explanations method (SHAP). Cross-validated receiver operating characteristic curves (cv-ROC) of the most contributive PET parameters were finally estimated and compared. RESULTS: The best machine learning model (k-NN) provided final cv-ROC of 0.81. According to SHAP analyses, visual PET metric was the most important contributor to the model overall performance, followed by the minimum between left and right striatal to occipital SUV ratio. The 10-time cv-ROC curves of visual, min SUVr or both showed quite similar performance (mean area under the ROC of 0.81, 0.81 and 0.79, respectively, for visual, min SUVr or both). CONCLUSION: Visual expert analysis remains the most relevant parameter to predict IPD diagnosis at 11 months of median clinical follow-up in 18F-FDOPA. The min SUV ratio appears interesting in the perspective of simple semi-automated diagnostic workflows.

Metabolic connectivity is associated with seizure outcome in surgically treated temporal lobe epilepsies: A 18F-FDG PET seed correlation analysis.

18F-FDG PET provides high sensitivity for the pre-surgical assessment of drug-resistant temporal lobe epilepsy (TLE). However, little is known about the metabolic connectivity of epileptogenic networks involved. This study therefore aimed to evaluate the association between metabolic connectivity and seizure outcome in surgically treated TLE. METHODS: The study included 107 right-handed patients that had undergone a presurgical interictal 18F-FDG PET assessment followed by an anterior temporal lobectomy and were classified according to seizure outcome 2 years after surgery. Metabolic connectivity was evaluated by seed correlation analysis in left and right epilepsy patients with a Class Engel IA or > IA outcome and compared to age-, sex- and handedness-matched healthy controls. RESULTS: Increased metabolic connectivity was observed in the >IA compared to the IA group within the operated temporal lobe (respective clusters of 7.5 vs 3.3 cm3 and 2.6 cm3 vs 2.2 cm3 in left and right TLE), and to a lower extent with the contralateral temporal lobe (1.2 vs 0.7 cm3 and 1.7 cm3 vs 0.7 cm3 in left and right TLE). Seed correlations provided added value for the estimated individual performance of seizure outcome over the group comparisons in left TLE (AUC of 0.74 vs 0.67). CONCLUSION: Metabolic connectivity is associated with outcome in surgically treated TLE with a strengthened epileptogenic connectome in patients with non-free-seizure outcomes. The added value of seed correlation analysis in left TLE underlines the importance of evaluating metabolic connectivity in network related diseases.

18F-FDOPA PET for the Noninvasive Prediction of Glioma Molecular Parameters: A Radiomics Study.

The assessment of gliomas by 18F-FDOPA PET imaging as an adjunct to MRI showed high performance by combining static and dynamic features to noninvasively predict the isocitrate dehydrogenase (IDH) mutations and the 1p/19q codeletion, which the World Health Organization classified as significant parameters in 2016. The current study evaluated whether other 18F-FDOPA PET radiomics features further improve performance and the contributions of each of these features to performance. Methods: Our study included 72 retrospectively selected, newly diagnosed glioma patients with 18F-FDOPA PET dynamic acquisitions. A set of 114 features, including conventional static features and dynamic features, as well as other radiomics features, were extracted and machine-learning models trained to predict IDH mutations and the 1p/19q codeletion. Models were based on a machine-learning algorithm built from stable, relevant, and uncorrelated features selected by hierarchic clustering followed by a bootstrapped feature selection process. Models were assessed by comparing area under the curve using a nested cross-validation approach. Feature importance was assessed using Shapley additive explanations values. Results: The best models were able to predict IDH mutations (logistic regression with L2 regularization) and the 1p/19q codeletion (support vector machine with radial basis function kernel) with an area under the curve of 0.831 (95% CI, 0.790-0.873) and 0.724 (95% CI, 0.669-0.782), respectively. For the prediction of IDH mutations, dynamic features were the most important features in the model (time to peak, 35.5%). In contrast, other radiomics features were the most useful for predicting the 1p/19q codeletion (up to 14.5% of importance for the small-zone low-gray-level emphasis). Conclusion:18F-FDOPA PET is an effective tool for the noninvasive prediction of glioma molecular parameters using a full set of amino-acid PET radiomics features. The contribution of each feature set shows the importance of systematically integrating dynamic acquisition for prediction of the IDH mutations as well as developing the use of radiomics features in routine practice for prediction of the 1p/19q codeletion.

Assessment of the routine reporting of very low-dose exercise-first myocardial perfusion SPECT from a large-scale real-world cohort and correlation with the subsequent reporting of coronary stenosis at angiography.

PURPOSE: Our study assesses the routine reporting of exercise ischemia using very low-dose exercise-first myocardial perfusion SPECT in a large number of patients and under real-life conditions, by evaluating correlations with the subsequent routine reporting of coronary stenosis by angiography and with factors that predict ischemia. METHODS: Data from 13,126 routine exercise MPI reports, from 11,952 patients (31% women), using very low doses of sestamibi and a high-sensitivity cardiac CZT camera, were extracted to assess the reporting of significant MPI-ischemia (> 1 left ventricular segment), to determine the MPI normalcy rate in a group with < 5% pretest probability of coronary artery disease (CAD) (n = 378), and to assess the ability of MPI to predict a > 50% coronary stenosis in patients with available coronary angiography reports in the 3 months after the MPI (n = 713). RESULTS: The median effective patient dose was 2.51 [IQR: 1.00-4.71] mSv. The normalcy rate was 98%, and the MPI-ischemia rate was independently predicted by a known CAD, the male gender, obesity, and a < 50% LV ejection fraction, ranging from 29.5% with all these risk factors represented to 1.5% when there were no risk factors. A > 50% coronary stenosis was significantly predicted by MPI-ischemia, less significantly for mild (odds ratio [95% confidence interval]: 1.61 [1.26-1.96]) than for moderate-to-severe MPI-ischemia (4.05 [3.53-4.57]) and was also impacted by having a known CAD (2.17 [1.83-2.51]), by a submaximal exercise test (1.48 [1.15-1.81]) and being ≥ 65 years of age (1.43 [1.11-1.76]). CONCLUSION: Ischemia detected using a very low-dose exercise-first MPI protocol in a large-scale clinical cohort and under real-life routine conditions is a highly significant predictor for the subsequent reporting of coronary stenosis, although this prediction is enhanced by other variables. This weakly irradiating approach is amenable to being repeated at shorter time intervals, in target patient groups with a high probability of MPI-ischemia.

Comparison between air and gas as tamponade in 25-gauge pars plana vitrectomy for primary superior rhegmatogenous retinal detachment.

BACKGROUND/OBJECTIVES: The aim of this study was to compare surgical outcomes and postoperative characteristics, between eyes that underwent pars plana vitrectomy (PPV) for RRD, with air or different gas agents as tamponade. SUBJECTS/METHODS: The records of 262 patients that underwent PPV for RRD with air or different gas tamponades and a follow-up of at least 6 months were examined. Only cases with superior retinal breaks were included. Demographic, pre-, intra- and postoperative characteristics including rate of recurrence and complications were analysed. RESULTS: 48 patients were treated with air and 214 were treated with gas. No differences were found in success rate between air and gas group at both 3 and 6 months (respectively, 93.8% vs 93.6 and 100% vs 100%, all P values > 0.05). Postoperative best-corrected visual acuity (BCVA) was significantly higher in the air group compared with the gas group 7 days and 1 month postoperatively (respectively, 0.2 ± 0.4 vs 2.6 ± 0.5, P < 0.001 and 0.1 ± 0.4 vs 0.4±0.9, P = 0.04). The occurrence ocular hypertension at 1 month postoperatively was significantly higher in the gas group compared with the air group (15.4 % vs 0%, P < 0.001). At 6 months, the prevalence of epiretinal membrane (ERM) was significantly higher in the gas group compared with air group (4.2% vs 16.8%, P = 0.02). CONCLUSIONS: Air was comparable to gas tamponades in terms of surgical outcome and BCVA at 6 months. In addition, air allowed an earlier visual recovery and resulted in a lower rate of postoperative ocular hypertension and ERM.

Brain 18F-FDG PET for the diagnosis of autoimmune encephalitis: a systematic review and a meta-analysis.

OBJECTIVE: To consolidate current understanding of detection sensitivity of brain 18F-FDG PET scans in the diagnosis of autoimmune encephalitis and to define specific metabolic imaging patterns for the most frequently occurring autoantibodies. METHODS: A systematic and exhaustive search of data available in the literature was performed by querying the PubMed/MEDLINE and Cochrane databases for the search terms: ((PET) OR (positron emission tomography)) AND ((FDG) OR (fluorodeoxyglucose)) AND ((encephalitis) OR (brain inflammation)). Studies had to satisfy the following criteria: (i) include at least ten pediatric or adult patients suspected or diagnosed with autoimmune encephalitis according to the current recommendations, (ii) specifically present 18F-FDG PET and/or morphologic imaging findings. The diagnostic 18F-FDG PET detection sensitivity in autoimmune encephalitis was determined for all cases reported in this systematic review, according to a meta-analysis following the PRISMA method, and selected publication quality was assessed with the QUADAS-2 tool. RESULTS: The search strategy identified 626 articles including references from publications. The detection sensitivity of 18F-FDG PET was 87% (80-92%) based on 21 publications and 444 patients included in the meta-analysis. We also report specific brain 18F-FDG PET imaging patterns for the main encephalitis autoantibody subtypes. CONCLUSION AND RELEVANCE: Brain 18F-FDG PET has a high detection sensitivity and should be included in future diagnostic autoimmune encephalitis recommendations. Specific metabolic 18F-FDG PET patterns corresponding to the main autoimmune encephalitis autoantibody subtypes further enhance the value of this diagnostic.

High-quality brain perfusion SPECT images may be achieved with a high-speed recording using 360° CZT camera.

OBJECTIVE: The aim of this study was to compare brain perfusion SPECT obtained from a 360° CZT and a conventional Anger camera. METHODS: The 360° CZT camera utilizing a brain configuration, with 12 detectors surrounding the head, was compared to a 2-head Anger camera for count sensitivity and image quality on 30-min SPECT recordings from a brain phantom and from 99mTc-HMPAO brain perfusion in 2 groups of 21 patients investigated with the CZT and Anger cameras, respectively. Image reconstruction was adjusted according to image contrast for each camera. RESULTS: The CZT camera provided more than 2-fold increase in count sensitivity, as compared with the Anger camera, as well as (1) lower sharpness indexes, giving evidence of higher spatial resolution, for both peripheral/central brain structures, with respective median values of 5.2%/3.7% versus 2.4%/1.9% for CZT and Anger camera respectively in patients (p < 0.01), and 8.0%/6.9% versus 6.2%/3.7% on phantom; and (2) higher gray/white matter contrast on peripheral/central structures, with respective ratio median values of 1.56/1.35 versus 1.11/1.20 for CZT and Anger camera respectively in patients (p < 0.05), and 2.57/2.17 versus 1.40/1.12 on phantom; and (3) no change in noise level. Image quality, scored visually by experienced physicians, was also significantly higher on CZT than on the Anger camera (+ 80%, p < 0.01), and all these results were unchanged on the CZT images obtained with only a 15 min recording time. CONCLUSION: The 360° CZT camera provides brain perfusion images of much higher quality than a conventional Anger camera, even with high-speed recordings, thus demonstrating the potential for repositioning brain perfusion SPECT to the forefront of brain imaging.

From metabolic connectivity to molecular connectivity: application to dopaminergic pathways.

INTRODUCTION: This study aims to reveal the feasibility and potential of molecular connectivity based on neurotransmission in comparison with the metabolic connectivity with an application to dopaminergic pathways. For this purpose, we propose to compare the neurotransmission connectivity findings using 123I-FP-CIT SPECT and 18F-FDOPA PET with the metabolic connectivity findings using 18F-FDG PET. METHODS: 18F-FDG PET and 123I-FP-CIT SPECT images from 47 subjects and 18F-FDOPA PET images from 177 subjects, who had no neurological or psychiatric disorders, were studied. Interregional correlation analyses were performed at the group level to determine the midbrain's connectivity via glucose metabolic rate using 18F-FDG PET and via dopaminergic binding potential using 123I-FP-CIT SPECT and 18F-FDOPA PET. SPM-T maps of each radiotracer were generated, and masks used to highlight the significant differences obtained among the imaging modalities and targets. RESULTS: The three dopaminergic pathways (i.e., nigrostriatal, mesolimbic, and mesocortical) were identified by 18F-FDG PET (1599 voxels, with a Tmax value of 12.6), 123I-FP-CIT SPECT (1120 voxels, with Tmax value of 5.1), and 18F-FDOPA PET (6054 voxels, with Tmax value of 11.7) for a T voxel threshold of 5.10, 2.80, and 5.10, respectively. Using the same T voxel threshold of 5.10, 18F-FDOPA PET showed more specific findings than 18F-FDG PET with less voxels identified outside these pathways (- 9323 voxels), whereas no significant voxels were obtained with 123I-FP-CIT SPECT at this threshold. CONCLUSION: The present study illustrates the feasibility and interest in using molecular connectivity with 18F-FDOPA PET for dopaminergic pathways. Such analyses could be applied to specific diseases involving the dopaminergic system.

Predicting the need for a reduced drug dose, at first prescription.

Prescribing the right drug with the right dose is a central tenet of precision medicine. We examined the use of patients' prior Electronic Health Records to predict a reduction in drug dosage. We focus on drugs that interact with the P450 enzyme family, because their dosage is known to be sensitive and variable. We extracted diagnostic codes, conditions reported in clinical notes, and laboratory orders from Stanford's clinical data warehouse to construct cohorts of patients that either did or did not need a dose change. After feature selection, we trained models to predict the patients who will (or will not) require a dose change after being prescribed one of 34 drugs across 23 drug classes. Overall, we can predict (AUC ≥ 0.70-0.95) a dose reduction for 23 drugs and 22 drug classes. Several of these drugs are associated with clinical guidelines that recommend dose reduction exclusively in the case of adverse reaction. For these cases, a reduction in dosage may be considered as a surrogate for an adverse reaction, which our system could indirectly help predict and prevent. Our study illustrates the role machine learning may take in providing guidance in setting the starting dose for drugs associated with response variability.

Scapholunate instability: improved detection with semi-automated kinematic CT analysis during stress maneuvers.

OBJECTIVES: To evaluate the diagnostic performance of radioulnar deviation (RUD) and clenching fist (CF) maneuvers for the evaluation of scapholunate dissociation (SLD) using quantitative kinematic CT. METHODS: Thirty-seven patients with suspected scapholunate instability were prospectively evaluated with kinematic CT. Two radiologists independently evaluated the SLD during RUD and CF maneuvers. Various dynamic parameters describing SLD were compared (maximal value, variation coefficient and range) in patients with and without scapholunate ligament ruptures confirmed by CT arthrography. RESULTS: SLD in CF varied from 3.17 ± 0.38 to 3.24 ± 0.80 mm in controls and from 4.11 ± 0.77 and 4.01 ± 0.85 mm in patients with scapholunate ligament ruptures for reader 1 and 2 (p < 0.009). SLD in RUD varied from 3.35 ± 0.51 and 3.01 ± 0.78 mm in controls and from 4.51 ± 1.26 to 4.42 ± 1.75 mm in patients with scapholunate ligament ruptures for reader 1 and 2 (p varied from 0.001 to 0.002). The inter-observer variability was better for RUD (ICC = 0.85 versus 0.6 for RUD and CF respectively). CONCLUSION: Analysis of SLD using kinematic CT has shown significant measurement differences between the groups with or without scapholunate instability with good diagnostic performance. KEY POINTS: • Kinematic CT can quantitatively assess scapholunate dissociation. • SLD analysis on kinematic CT has excellent reproducibility with radioulnar deviation maneuver. • Scapholunate dissociation was significantly different in patients with and without instability. • Diagnostic performance for scapholunate instability identification was better with radioulnar deviation.

Brain PET substrate of impulse control disorders in Parkinson's disease: A metabolic connectivity study.

Impulse control disorders (ICDs) have received increased attention in Parkinson's disease (PD) because of potentially dramatic consequences. Their physiopathology, however, remains incompletely understood. An overstimulation of the mesocorticolimbic system has been reported, while a larger network has recently been suggested. The aim of this study is to specifically describe the metabolic PET substrate and related connectivity changes in PD patients with ICDs. Eighteen PD patients with ICDs and 18 PD patients without ICDs were evaluated using cerebral 18F-fluorodeoxyglucose positron emission tomography. SPM-T maps comparisons were performed between groups and metabolic connectivity was evaluated by interregional correlation analysis (IRCA; p < .005, uncorrected; k > 130) and by graph theory (p < .05). PD patients with ICDs had relative increased metabolism in the right middle and inferior temporal gyri compared to those without ICDs. The connectivity of this area was increased mostly with the mesocorticolimbic system, positively with the orbitofrontal region, and negatively with both the right parahippocampus and the left caudate (IRCA). Moreover, the betweenness centrality of this area with the mesocorticolimbic system was lost in patients with ICDs (graph analysis). ICDs are associated in PD with the dysfunction of a network exceeding the mesocorticolimbic system, and especially the caudate, the parahippocampus, and the orbitofrontal cortex, remotely including the right middle and inferior temporal gyri. This latest area loses its central place with the mesocorticolimbic system through a connectivity dysregulation.

A high 18F-FDOPA uptake is associated with a slow growth rate in diffuse Grade II-III gliomas.

OBJECTIVE: In diffuse Grade II-III gliomas, a high 3,4-dihydroxy-6-(18F)-fluoro-L-phenylalanine (18F-FDOPA) positron emission tomography (PET) uptake, with a standardized uptake value (SUVmax)/contralateral brain tissue ratio greater than 1.8, was previously found to be consistently associated with the presence of an isocitrate dehydrogenase (IDH) mutation, whereas this mutation is typically associated with a better prognosis. This pilot study was aimed to ascertain the prognostic value of this high 18F-FDOPA uptake in diffuse Grade II-III gliomas with regard to the velocity of diameter expansion (VDE), which represents an established landmark of better prognosis when below 4 mm per year. METHODS: 20 patients (42 ± 10 years, 10 female) with newly-diagnosed diffuse Grade II-III gliomas (17 with IDH mutation) were retrospectively included. All had a 18F-FDOPA PET, quantified with SUVmax ratio, along with a serial MRI enabling VDE determination. RESULTS: SUVmax ratio was above 1.8 in 5 patients (25%) all of whom had a VDE <4 mm/year (100%) and IDH mutation (100%). Moreover, a SUVmax ratio above 1.8 was associated with higher rates of VDE <4 mm/year in the overall population (45 vs 0%, p = 0.04) and also in the subgroup of patients with IDH mutation (45 vs 0%, p = 0.10). CONCLUSION: This pilot study shows that in diffuse Grade II-III gliomas, a high 18F-FDOPA uptake would be predictive of low tumour growth, with a different prognostic significance than IDH mutation. Advances in knowledge: 18F-FDOPA PET in a single session imaging could have prognostic value in initial diagnosis of diffuse Grade II-III gliomas.

Cross-sectional variations of white and grey matter in older hypertensive patients with subjective memory complaints.

Mild cognitive impairment and Alzheimer's dementia involve a grey matter disease, quantifiable by 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET), but also white matter damage, evidenced by diffusion tensor magnetic resonance imaging (DTI), which may play an additional pathogenic role. This study aimed to determine whether such DTI and PET variations are also interrelated in a high-risk population of older hypertensive patients with only subjective memory complaints (SMC). Sixty older hypertensive patients (75 ± 5 years) with SMC were referred to DTI and FDG-PET brain imaging, executive and memory tests, as well as peripheral and central blood pressure (BP) measurements. Mean apparent diffusion coefficient (ADCmean) was determined in overall white matter and correlated with the grey matter distribution of the metabolic rate of glucose (CMRGlc) using whole-brain voxel-based analyses of FDG-PET images. ADCmean was variable between individuals, ranging from 0.82 to 1.01.10- 3 mm2 sec- 1, and mainly in relation with CMRGlc of areas involved in Alzheimer's disease such as internal temporal areas, posterior associative junctions, posterior cingulum but also insulo-opercular areas (global correlation coefficient: - 0.577, p < 0.001). Both the ADCmean and CMRGlc of the interrelated grey matter areas were additionally and concordantly linked to the results of executive and memory tests and to systolic central BP (all p < 0.05). Altogether, our findings show that cross-sectional variations in overall white brain matter are linked to the metabolism of Alzheimer-like cortical areas and to cognitive performance in older hypertensive patients with only subjective memory complaints. Additional relationships with central BP strengthen the hypothesis of a contributing pathogenic role of hypertension.

Per-Arnt-Sim kinase regulates pancreatic duodenal homeobox-1 protein stability via phosphorylation of glycogen synthase kinase 3ß in pancreatic ß-cells.

In pancreatic ß-cells, glucose induces the binding of the transcription factor pancreatic duodenal homeobox-1 (PDX-1) to the insulin gene promoter to activate insulin gene transcription. At low glucose levels, glycogen synthase kinase 3ß (GSK3ß) is known to phosphorylate PDX-1 on C-terminal serine residues, which triggers PDX-1 proteasomal degradation. We previously showed that the serine/threonine Per-Arnt-Sim domain-containing kinase (PASK) regulates insulin gene transcription via PDX-1. However, the mechanisms underlying this regulation are unknown. In this study, we aimed to identify the role of PASK in the regulation of PDX-1 phosphorylation, protein expression, and stability in insulin-secreting cells and isolated rodent islets of Langerhans. We observed that glucose induces a decrease in overall PDX-1 serine phosphorylation and that overexpression of WT PASK mimics this effect. In vitro, PASK directly phosphorylates GSK3ß on its inactivating phosphorylation site Ser(9). Overexpression of a kinase-dead (KD), dominant negative version of PASK blocks glucose-induced Ser(9) phosphorylation of GSK3ß. Accordingly, GSK3ß Ser(9) phosphorylation is reduced in islets from pask-null mice. Overexpression of WT PASK or KD GSK3ß protects PDX-1 from degradation and results in increased PDX-1 protein abundance. Conversely, overexpression of KD PASK blocks glucose-induction of PDX-1 protein. We conclude that PASK phosphorylates and inactivates GSK3ß, thereby preventing PDX-1 serine phosphorylation and alleviating GSK3ß-mediated PDX-1 protein degradation in pancreatic ß-cells.