Integration and evaluation of chest X-ray artificial intelligence in clinical practice.

Purpose: To integrate and evaluate an artificial intelligence (AI) system that assists in checking endotracheal tube (ETT) placement on chest x-rays (CXRs) in clinical practice. Approach: In clinical use over 17 months, 214 CXR images were ordered to check ETT placement with AI assistance by intensive care unit (ICU) physicians. The system was built on the SimpleMind Cognitive AI platform and integrated into a clinical workflow. It automatically identified the ETT and checked its placement relative to the trachea and carina. The ETT overlay and misplacement alert messages generated by the AI system were compared with radiology reports as the reference. A survey study was also conducted to evaluate usefulness of the AI system in clinical practice. Results: The alert messages indicating that either the ETT was misplaced or not detected had a positive predictive value of 42% (21/50) and negative predictive value of 98% (161/164) based on the radiology reports. In the survey, radiologist and ICU physician users indicated that they agreed with the AI outputs and that they were useful. Conclusions: The AI system performance in real-world clinical use was comparable to that seen in previous experiments. Based on this and physician survey results, the system can be deployed more widely at our institution, using insights gained from this evaluation to make further algorithm improvements and quality assurance of the AI system.

Automated Endotracheal Tube Placement Check Using Semantically Embedded Deep Neural Networks.

RATIONALE AND OBJECTIVES: To develop artificial intelligence (AI) system that assists in checking endotracheal tube (ETT) placement on chest X-rays (CXRs) and evaluate whether it can move into clinical validation as a quality improvement tool. MATERIALS AND METHODS: A retrospective data set including 2000 de-identified images from intensive care unit patients was split into 1488 for training and 512 for testing. AI was developed to automatically identify the ETT, trachea, and carina using semantically embedded neural networks that combine a declarative knowledge base with deep neural networks. To check the ETT tip placement, a "safe zone" was computed as the region inside the trachea and 3-7 cm above the carina. Two AI outputs were evaluated: (1) ETT overlay, (2) ETT misplacement alert messages. Clinically relevant performance metrics were compared against prespecified thresholds of >85% overlay accuracy and positive predictive value (PPV) > 30% and negative predictive value NPV > 95% for alerts to move into clinical validation. RESULTS: An ETT was present in 285 of 512 test cases. The AI detected 95% (271/285) of ETTs, 233 (86%) of these with accurate tip localization. The system (correctly) did not generate an ETT overlay in 221/227 CXRs where the tube was absent for an overall overlay accuracy of 89% (454/512). The alert messages indicating that either the ETT was misplaced or not detected had a PPV of 83% (265/320) and NPV of 98% (188/192). CONCLUSION: The chest X-ray AI met prespecified performance thresholds to move into clinical validation.

Probing Estrogen Sulfotransferase-Mediated Inflammation with [11C]-PiB in the Living Human Brain.

BACKGROUND: 2-(4'- [11C]Methylaminophenyl)-6-hydroxybenzothiazole ([11C]-PiB), purportedly a specific imaging agent for cerebral amyloid-ß plaques, is a specific, high affinity substrate for estrogen sulfotransferase (SULT1E1), an enzyme that regulates estrogen homeostasis. OBJECTIVE: In this work, we use positron emission tomography (PET) imaging with [11C]-PiB to assess the functional activity of SULT1E1 in the brain of moyamoya disease patients. METHODS: Ten moyamoya subjects and five control patients were evaluated with [11C]-PiB PET and structural MRI scans. Additionally, a patient with relapsing-remitting multiple sclerosis (RRMS) received [11C]-PiB PET scans before and after steroidal and immunomodulatory therapy. Parametric PET images were established to assess SULT1E1 distribution in the inflamed brain tissue. RESULTS: Increased [11C]-PiB SRTM DVR in the thalamus, pons, corona radiata, and internal capsule of moyamoya cohort subjects was observed in comparison with controls (p ≤ 0.01). This was observed in patients without treatment, with collateralization, and also after radiation. The post-treatment [11C]-PiB PET scan in one RRMS patient also revealed substantially reduced subcortical brain inflammation. In validation studies, [11C]-PiB autoradiography signal in the peri-infarct area of the rat middle cerebral arterial occlusion stroke model was shown to correlate with SULT1E1 immunohistochemistry. CONCLUSION: Strong [11C]-PiB PET signal associated with intracranial inflammation in the moyamoya syndrome cohort and a single RRMS patient appears consistent with functional imaging of SULT1E1 activity in the human brain. This preliminary work offers substantial and direct evidence that significant [11C]-PiB PET focal signals can be obtained from the living human brain with intracranial inflammation, signals not attributable to amyloid-ß plaques.

The Value of In Vitro Binding as Predictor of In Vivo Results: A Case for [18F]FDDNP PET.

PURPOSE: Caution is warranted when in vitro results of biomarkers labeled with tritium were perfunctorily used to criticize in vivo data and conclusions derived with the same tracers labeled with positron emitters and positron emission tomography (PET). This concept is illustrated herein with the PET utilization of [18F]FDDNP, a biomarker used for in vivo visualization of ß-amyloid and tau protein neuroaggregates in humans, later contradicted by in vitro data reported with [3H]FDDNP. In this investigation, we analyze the multiple factors involved in the experimental design of the [3H]FDDNP in vitro study that led to the erroneous interpretation of results. PROCEDURE: The present work describes full details on the synthesis, characterization, purity, and kinetics of radiolytic stability of [3H]FDDNP. The optimal in vitro conditions for detecting tau and ß-amyloid protein aggregates using macroscopic and microscopic autoradiography with both [18F]FDDNP and [3H]FDDNP are also presented. Macroscopic autoradiography determinations were performed with [3H]FDDNP of verified purity using established methods described previously in the literature. RESULTS: The autoradiographic results using phosphate buffered saline (PBS) with less than 1 % EtOH and pure, freshly prepared [3H]FDDNP compared with the earlier reported data using [3H]FDDNP of undetermined purity and PBS in 10 % EtOH demonstrate the critical importance of rigorous experimental design for meaningful in vitro determinations. [18F]FDDNP binding to both amyloid plaques and neurofibrillary tangles was confirmed by amyloid and tau immunohistochemical stains of adjacent tissues. CONCLUSIONS: This work illustrates the sensitivity of in vitro techniques to various experimental conditions and underscores that conclusions obtained from translational in vitro to in vivo determinations must always be performed with extreme care to avoid wrong interpretations that can be perpetuated and assumed without further analysis.

FDDNP-PET Tau Brain Protein Binding Patterns in Military Personnel with Suspected Chronic Traumatic Encephalopathy1.

BACKGROUND: Our group has shown that in vivo tau brain binding patterns from FDDNP-PET scans in retired professional football players with suspected chronic traumatic encephalopathy differ from those of tau and amyloid aggregate binding observed in Alzheimer's disease (AD) patients and cognitively-intact controls. OBJECTIVE: To compare these findings with those from military personnel with histories of mild traumatic brain injury(mTBI). METHODS: FDDNP-PET brain scans were compared among 7 military personnel and 15 retired players with mTBI histories and cognitive and/or mood symptoms, 24 AD patients, and 28 cognitively-intact controls. Nonparametric ANCOVAs with Tukey-Kramer adjusted post-hoc comparisons were used to test for significant differences in regional FDDNP binding among subject groups. RESULTS: FDDNP brain binding was higher in military personnel compared to controls in the amygdala, midbrain, thalamus, pons, frontal and anterior and posterior cingulate regions (p < 0.01-0.0001). Binding patterns in the military personnel were similar to those of the players except for the amygdala and striatum (binding higher in players; p = 0.02-0.003). Compared with the AD group, the military personnel showed higher binding in the midbrain (p = 0.0008) and pons (p = 0.002) and lower binding in the medial temporal, lateral temporal, and parietal regions (all p = 0.02). CONCLUSION: This first study of in vivo tau and amyloid brain signals in military personnel with histories of mTBI shows binding patterns similar to those of retired football players and distinct from the binding patterns in AD and normal aging, suggesting the potential value of FDDNP-PET for early detection and treatment monitoring in varied at-risk populations.

Regional association of pCASL-MRI with FDG-PET and PiB-PET in people at risk for autosomal dominant Alzheimer's disease.

Autosomal dominant Alzheimer's disease (ADAD) is a small subset of Alzheimer's disease that is genetically determined with 100% penetrance. It provides a valuable window into studying the course of pathologic processes that leads to dementia. Arterial spin labeling (ASL) MRI is a potential AD imaging marker that non-invasively measures cerebral perfusion. In this study, we investigated the relationship of cerebral blood flow measured by pseudo-continuous ASL (pCASL) MRI with measures of cerebral metabolism (FDG PET) and amyloid deposition (Pittsburgh Compound B (PiB) PET). Thirty-one participants at risk for ADAD (age 39 ± 13 years, 19 females) were recruited into this study, and 21 of them received both MRI and FDG and PiB PET scans. Considerable variability was observed in regional correlations between ASL-CBF and FDG across subjects. Both regional hypo-perfusion and hypo-metabolism were associated with amyloid deposition. Cross-sectional analyses of each biomarker as a function of the estimated years to expected dementia diagnosis indicated an inverse relationship of both perfusion and glucose metabolism with amyloid deposition during AD development. These findings indicate that neurovascular dysfunction is associated with amyloid pathology, and also indicate that ASL CBF may serve as a sensitive early biomarker for AD. The direct comparison among the three biomarkers provides complementary information for understanding the pathophysiological process of AD.

Memory and Brain Amyloid and Tau Effects of a Bioavailable Form of Curcumin in Non-Demented Adults: A Double-Blind, Placebo-Controlled 18-Month Trial.

OBJECTIVE: Because curcumin's anti-inflammatory properties may protect the brain from neurodegeneration, we studied its effect on memory in non-demented adults and explored its impact on brain amyloid and tau accumulation using 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile positron emission tomography (FDDNP-PET). METHODS: Forty subjects (age 51-84 years) were randomized to a bioavailable form of curcumin (Theracurmin® containing 90 mg of curcumin twice daily [N = 21]) or placebo (N = 19) for 18 months. Primary outcomes were verbal (Buschke Selective Reminding Test [SRT]) and visual (Brief Visual Memory Test-Revised [BVMT-R]) memory, and attention (Trail Making A) was a secondary outcome. FDDNP-PET signals (15 curcumin, 15 placebo) were determined in amygdala, hypothalamus, medial and lateral temporal, posterior cingulate, parietal, frontal, and motor (reference) regions. Mixed effects general linear models controlling for age and education, and effect sizes (ES; Cohen's d) were estimated. RESULTS: SRT Consistent Long-Term Retrieval improved with curcumin (ES = 0.63, p = 0.002) but not with placebo (ES = 0.06, p = 0.8; between-group: ES = 0.68, p = 0.05). Curcumin also improved SRT Total (ES = 0.53, p = 0.002), visual memory (BVMT-R Recall: ES = 0.50, p = 0.01; BVMT-R Delay: ES = 0.51, p = 0.006), and attention (ES = 0.96, p < 0.0001) compared with placebo (ES = 0.28, p = 0.1; between-group: ES = 0.67, p = 0.04). FDDNP binding decreased significantly in the amygdala with curcumin (ES = -0.41, p = 0.04) compared with placebo (ES = 0.08, p = 0.6; between-group: ES = 0.48, p = 0.07). In the hypothalamus, FDDNP binding did not change with curcumin (ES = -0.30, p = 0.2), but increased with placebo (ES = 0.26, p = 0.05; between-group: ES = 0.55, p = 0.02). CONCLUSIONS: Daily oral Theracurmin may lead to improved memory and attention in non-demented adults. The FDDNP-PET findings suggest that symptom benefits are associated with decreases in amyloid and tau accumulation in brain regions modulating mood and memory.

Postmortem Autopsy-Confirmation of Antemortem [F-18]FDDNP-PET Scans in a Football Player With Chronic Traumatic Encephalopathy.

Currently, only presumptive diagnosis of chronic traumatic encephalopathy (CTE) can be made in living patients. We present a modality that may be instrumental to the definitive diagnosis of CTE in living patients based on brain autopsy confirmation of [F-18]FDDNP-PET findings in an American football player with CTE. [F-18]FDDNP-PET imaging was performed 52 mo before the subject's death. Relative distribution volume parametric images and binding values were determined for cortical and subcortical regions of interest. Upon death, the brain was examined to identify the topographic distribution of neurodegenerative changes. Correlation between neuropathology and [F-18]FDDNP-PET binding patterns was performed using Spearman rank-order correlation. Mood, behavioral, motor, and cognitive changes were consistent with chronic traumatic myeloencephalopathy with a 22-yr lifetime risk exposure to American football. There were tau, amyloid, and TDP-43 neuropathological substrates in the brain with a differential topographically selective distribution. [F-18]FDDNP-PET binding levels correlated with brain tau deposition (rs = 0.59, P = .02), with highest relative distribution volumes in the parasagittal and paraventricular regions of the brain and the brain stem. No correlation with amyloid or TDP-43 deposition was observed. [F-18]FDDNP-PET signals may be consistent with neuropathological patterns of tau deposition in CTE, involving areas that receive the maximal shearing, angular-rotational acceleration-deceleration forces in American football players, consistent with distinctive and differential topographic vulnerability and selectivity of CTE beyond brain cortices, also involving midbrain and limbic areas. Future studies are warranted to determine whether differential and selective [F-18]FDDNP-PET may be useful in establishing a diagnosis of CTE in at-risk patients.

A semi-automated workflow solution for multimodal neuroimaging: application to patients with traumatic brain injury.

Traumatic brain injury (TBI) is a major cause of mortality and morbidity, placing a significant financial burden on the healthcare system worldwide. Non-invasive neuroimaging technologies have been playing a pivotal role in the study of TBI, providing important information for surgical planning and patient management. Advances in understanding the basic mechanisms and pathophysiology of the brain following TBI are hindered by a lack of reliable image analysis methods for accurate quantitative assessment of TBI-induced structural and pathophysiological changes seen on anatomical and functional images obtained from multiple imaging modalities. Conventional region-of-interest (ROI) analysis based on manual labeling of brain regions is time-consuming and the results could be inconsistent within and among investigators. In this study, we propose a workflow solution framework that combined the use of non-linear spatial normalization of structural brain images and template-based anatomical labeling to automate the ROI analysis process. The proposed workflow solution is applied to dynamic PET scanning with 15O-water (0-10 min) and 18F-FDDNP (0-6 min) for measuring cerebral blood flow in patients with TBI.

In vivo characterization of chronic traumatic encephalopathy using [F-18]FDDNP PET brain imaging.

Chronic traumatic encephalopathy (CTE) is an acquired primary tauopathy with a variety of cognitive, behavioral, and motor symptoms linked to cumulative brain damage sustained from single, episodic, or repetitive traumatic brain injury (TBI). No definitive clinical diagnosis for this condition exists. In this work, we used [F-18]FDDNP PET to detect brain patterns of neuropathology distribution in retired professional American football players with suspected CTE (n = 14) and compared results with those of cognitively intact controls (n = 28) and patients with Alzheimer's dementia (AD) (n = 24), a disease that has been cognitively associated with CTE. [F-18]FDDNP PET imaging results in the retired players suggested the presence of neuropathological patterns consistent with models of concussion wherein brainstem white matter tracts undergo early axonal damage and cumulative axonal injuries along subcortical, limbic, and cortical brain circuitries supporting mood, emotions, and behavior. This deposition pattern is distinctively different from the progressive pattern of neuropathology [paired helical filament (PHF)-tau and amyloid-ß] in AD, which typically begins in the medial temporal lobe progressing along the cortical default mode network, with no or minimal involvement of subcortical structures. This particular [F-18]FDDNP PET imaging pattern in cases of suspected CTE also is primarily consistent with PHF-tau distribution observed at autopsy in subjects with a history of mild TBI and autopsy-confirmed diagnosis of CTE.

A semi-automated technique determining the liver standardized uptake value reference for tumor delineation in FDG PET-CT.

BACKGROUND: 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)-computed tomography (CT) has been an essential modality in oncology. We propose a semi-automated algorithm to objectively determine liver standardized uptake value (SUV), which is used as a threshold for tumor delineation. METHODS: A large spherical volume of interest (VOI) was placed manually to roughly enclose the right lobe (RL) of the liver. For each voxel in this VOI, a coefficient of variation of voxel values (CVv) was calculated for neighboring voxels within a radius of d/2. The voxel with the minimum CVv was then selected, where a 30-mm spherical VOI was placed at that voxel in accordance with PERCIST criteria. Two nuclear medicine physicians independently defined 30-mm VOIs manually on 124 studies in 62 patients to generate the standard values, against which the results from the new method were compared. RESULTS: The semi-automated method was successful in determining the liver SUV that was consistent between the two physicians in all the studies (d = 80 mm). The liver SUV threshold (mean +3 SD within 30-mm VOI) determined by the new semi-automated method (3.12±0.61) was not statistically different from those determined by the manual method (Physician-1: 3.14±0.58, Physician-2: 3.15±0.58). The semi-automated method produced tumor volumes that were not statistically different from those by experts' manual operation. Furthermore, the volume change in the two sequential studies had no statistical difference between semi-automated and manual methods. CONCLUSIONS: Our semi-automated method could define the liver SUV robustly as the threshold value used for tumor volume measurements according to PERCIST. The method could avoid possible subjective bias of manual liver VOI placement and is thus expected to improve clinical performance of volume-based parameters for prediction of cancer treatment response.

Automated movement correction for dynamic PET/CT images: evaluation with phantom and patient data.

Head movement during a dynamic brain PET/CT imaging results in mismatch between CT and dynamic PET images. It can cause artifacts in CT-based attenuation corrected PET images, thus affecting both the qualitative and quantitative aspects of the dynamic PET images and the derived parametric images. In this study, we developed an automated retrospective image-based movement correction (MC) procedure. The MC method first registered the CT image to each dynamic PET frames, then re-reconstructed the PET frames with CT-based attenuation correction, and finally re-aligned all the PET frames to the same position. We evaluated the MC method's performance on the Hoffman phantom and dynamic FDDNP and FDG PET/CT images of patients with neurodegenerative disease or with poor compliance. Dynamic FDDNP PET/CT images (65 min) were obtained from 12 patients and dynamic FDG PET/CT images (60 min) were obtained from 6 patients. Logan analysis with cerebellum as the reference region was used to generate regional distribution volume ratio (DVR) for FDDNP scan before and after MC. For FDG studies, the image derived input function was used to generate parametric image of FDG uptake constant (Ki) before and after MC. Phantom study showed high accuracy of registration between PET and CT and improved PET images after MC. In patient study, head movement was observed in all subjects, especially in late PET frames with an average displacement of 6.92 mm. The z-direction translation (average maximum = 5.32 mm) and x-axis rotation (average maximum = 5.19 degrees) occurred most frequently. Image artifacts were significantly diminished after MC. There were significant differences (P<0.05) in the FDDNP DVR and FDG Ki values in the parietal and temporal regions after MC. In conclusion, MC applied to dynamic brain FDDNP and FDG PET/CT scans could improve the qualitative and quantitative aspects of images of both tracers.

Factors affecting tumor (18) F-FDG uptake in longitudinal mouse PET studies.

BACKGROUND: Many biological factors of 2-[(18) F]fluoro-2-deoxy-d-glucose ((18) F-FDG) in blood can affect (18) F-FDG uptake in tumors. In this study, longitudinal (18) F-FDG positron emission tomography (PET) studies were performed on tumor-bearing mice to investigate the effect of blood glucose level and tumor size on (18) F-FDG uptake in tumors. METHODS: Six- to eight-week-old severe combined immunodeficiency mice were implanted with glioblastoma U87 (n = 8) or adenocarcinoma MDA-MB-231 (MDA) (n = 11) in the shoulder. When the tumor diameter was approximately 2.5 mm, a 60-min dynamic (18) F-FDG PET scan was performed weekly until the tumor diameter reached 10 mm. Regions of interests were defined in major organs and tumor. A plasma curve was derived based on a modeling method that utilizes the early heart time-activity curve and a late-time blood sample. The (18) F-FDG uptake constant K i was calculated using Patlak analysis on the tumors without an apparent necrotic center shown in the PET images. For each tumor type, the measured K i was corrected for partial volume (PV), and multivariate regression analysis was performed to examine the effects of blood glucose level ([Glc]) and tumor growth. Corrected Akaike's information criterion was used to determine the best model. RESULTS: The regression model that best fit the PV-corrected K i for U87 data was K i /RC = (1/[Glc]) × (0.27 ± 0.027) mL/min/mL (where [Glc] is in mmol/L), and for MDA, it was K i /RC = (0.04 ± 0.005) mL/min/mL, where K i /RC denotes the PV-corrected K i using an individual recovery coefficient (RC). The results indicated that (18) F-FDG K i /RC for U87 was inversely related to [Glc], while [Glc] had no effect on (18) F-FDG K i /RC of MDA. After the effects of PV and [Glc] were accounted for, the data did not support any increase of (18) F-FDG K i as the tumor (of either type) grew larger in size. CONCLUSIONS: The effect of [Glc] on the tumor (18) F-FDG K i was tumor-dependent. PV- and [Glc]-corrected (18) F-FDG K i did not show significant increase as the tumor of either type grew in size.

Postmortem 3-D brain hemisphere cortical tau and amyloid-ß pathology mapping and quantification as a validation method of neuropathology imaging.

This work is aimed at correlating pre-mortem [18F]FDDNP positron emission tomography (PET) scan results in a patient with dementia with Lewy bodies (DLB), with cortical neuropathology distribution determined postmortem in three physical dimensions in whole brain coronal sections. Analysis of total amyloid-ß (Aß) distribution in frontal cortex and posterior cingulate gyrus confirmed its statistically significant correlation with cortical [18F]FDDNP PET binding values (distribution volume ratios, DVR) (p < 0.001, R = 0.97, R2 = 0.94). Neurofibrillary tangle (NFT) distribution correlated significantly with cortical [18F]FDDNP PET DVR in the temporal lobe (p < 0.001, R = 0.87, R2 = 0.76). Linear combination of Aß and NFT densities was highly predictive of [18F]FDDNP PET DVR through all analyzed regions of interest (p < 0.0001, R = 0.92, R2 = 0.85), and both densities contributed significantly to the model. Lewy bodies were present at a much lower level than either Aß or NFTs and did not significantly contribute to the in vivo signal. [18F]FDG PET scan results in this patient were consistent with the distinctive DLB pattern of hypometabolism. This work offers a mapping brain model applicable to all imaging probes for verification of imaging results with Aß and/or tau neuropathology brain distribution using immunohistochemistry, fluorescence microscopy, and autoradiography.

Improved derivation of input function in dynamic mouse [18F]FDG PET using bladder radioactivity kinetics.

PURPOSE: Accurate determination of the plasma input function (IF) is essential for absolute quantification of physiological parameters in positron emission tomography (PET). However, it requires an invasive and tedious procedure of arterial blood sampling that is challenging in mice because of the limited blood volume. In this study, a hybrid modeling approach is proposed to estimate the plasma IF of 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) in mice using accumulated radioactivity in urinary bladder together with a single late-time blood sample measurement. METHODS: Dynamic PET scans were performed on nine isoflurane-anesthetized male C57BL/6 mice after a bolus injection of [18F]FDG at the lateral caudal vein. During a 60- or 90-min scan, serial blood samples were taken from the femoral artery. Image data were reconstructed using filtered backprojection with computed tomography-based attenuation correction. Total accumulated radioactivity in the urinary bladder at late times was fitted to a renal compartmental model with the last blood sample and a one-exponential function that described the [18F]FDG clearance in blood. Multiple late-time blood sample estimates were calculated by the blood [18F]FDG clearance equation. A sum of four-exponentials was assumed for the plasma IF that served as a forcing function to all tissues. The estimated plasma IF was obtained by simultaneously fitting the [18F]FDG model to the time-activity curves (TACs) of liver and muscle and the forcing function to early (0-1 min) left-ventricle data (corrected for delay, dispersion, partial-volume effects, and erythrocyte uptake) and the late-time blood estimates. Using only the blood sample collected at the end of the study to estimate the IF and the use of liver TAC as an alternative IF were also investigated. RESULTS: The area under the plasma IFs calculated for all studies using the hybrid approach was not significantly different from that using all blood samples. [18F]FDG uptake constants in brain, myocardium, skeletal muscle, and liver computed by the Patlak analysis using estimated and measured plasma IFs were in excellent agreement (slope∼1; R2>0.983). The IF estimated using only the last blood sample drawn at the end of the study and the use of liver TAC as the plasma IF provided less reliable results. CONCLUSIONS: The estimated plasma IFs obtained with the hybrid method agreed well with those derived from arterial blood sampling. Importantly, the proposed method obviates the need of arterial catheterization, making it possible to perform repeated dynamic [18F]FDG PET studies on the same animal. Liver TAC is unsuitable as an input function for absolute quantification of [18F]FDG PET data.

Comparative evaluation of Logan and relative-equilibrium graphical methods for parametric imaging of dynamic [18F]FDDNP PET determinations.

UNLABELLED: Logan graphical analysis with cerebellum as reference region has been widely used for the estimation of the distribution volume ratio (DVR) of [(18)F]FDDNP as a measure of amyloid burden and tau deposition in human brain because of its simplicity and computational ease. However, spurious parametric DVR images may be produced with shorter scanning times and when the noise level is high. In this work, we have characterized a relative-equilibrium-based (RE) graphical method against the Logan analysis for parametric imaging and region-of-interest (ROI) analysis. METHODS: Dynamic [(18)F]FDDNP PET scans were performed on 9 control subjects and 12 patients diagnosed with Alzheimer's disease. Using the cerebellum as reference input, regional DVR estimates were derived using both the Logan analysis and the RE plot approach. Effects on DVR estimates obtained at voxel and ROI levels by both graphical approaches using data in different time windows were investigated and compared with the standard values derived using the Logan analysis on a voxel-by-voxel basis for the time window of 35-125 min used in previous studies. RESULTS: Larger bias and variability were observed for DVR estimates obtained by the Logan graphical analysis at the voxel level when short time windows (85-125 and 45-65 min) were used, because of high noise levels in voxel-wise parametric imaging. However, when the Logan graphical analysis was applied at the ROI level over those short time windows, the DVR estimates did not differ significantly from the standard values derived using the Logan analysis on the voxel level for the time window of 35-125 min, and their bias and variability were remarkably lower. Conversely, the RE plot approach was more robust in providing DVR estimates with less bias and variability even when short time windows were used. The DVR estimates obtained at voxel and ROI levels were consistent. No significant differences were observed in DVR estimates obtained by the RE plot approach for all paired comparisons with the standard values. CONCLUSIONS: The RE plot approach provides less noisy parametric images and gives consistent and reliable regional DVR estimates at both voxel and ROI levels, indicating that it is preferred over the Logan graphical analysis for analyzing [(18)F]FDDNP PET data.

Influence of dietary state and insulin on myocardial, skeletal muscle and brain [F]-fluorodeoxyglucose kinetics in mice.

BACKGROUND: We evaluated the effect of insulin stimulation and dietary changes on myocardial, skeletal muscle and brain [(18)F]-fluorodeoxyglucose (FDG) kinetics and uptake in vivo in intact mice. METHODS: Mice were anesthetized with isoflurane and imaged under different conditions: non-fasted (n = 7; "controls"), non-fasted with insulin (2 IU/kg body weight) injected subcutaneously immediately prior to FDG (n = 6), fasted (n = 5), and fasted with insulin injection (n = 5). A 60-min small-animal PET with serial blood sampling and kinetic modeling was performed. RESULTS: We found comparable FDG standardized uptake values (SUVs) in myocardium in the non-fasted controls and non-fasted-insulin injected group (SUV 45-60 min, 9.58 ± 1.62 vs. 9.98 ± 2.44; p = 0.74), a lower myocardial SUV was noted in the fasted group (3.48 ± 1.73; p < 0.001). In contrast, the FDG uptake rate constant (K(i)) for myocardium increased significantly by 47% in non-fasted mice by insulin (13.4 ± 3.9 ml/min/100 g vs. 19.8 ± 3.3 ml/min/100 g; p = 0.030); in fasted mice, a lower myocardial K(i) as compared to controls was observed (3.3 ± 1.9 ml/min/100 g; p < 0.001). Skeletal muscle SUVs and K(i) values were increased by insulin independent of dietary state, whereas in the brain, those parameters were not influenced by fasting or administration of insulin. Fasting led to a reduction in glucose metabolic rate in the myocardium (19.41 ± 5.39 vs. 3.26 ± 1.97 mg/min/100 g; p < 0.001), the skeletal muscle (1.06 ± 0.34 vs. 0.34 ± 0.08 mg/min/100 g; p = 0.001) but not the brain (3.21 ± 0.53 vs. 2.85 ±0.25 mg/min/100 g; p = 0.19). CONCLUSIONS: Changes in organ SUVs, uptake rate constants and metabolic rates induced by fasting and insulin administration as observed in intact mice by small-animal PET imaging are consistent with those observed in isolated heart/muscle preparations and, more importantly, in vivo studies in larger animals and in humans. When assessing the effect of insulin on the myocardial glucose metabolism of non-fasted mice, it is not sufficient to just calculate the SUV - dynamic imaging with kinetic modeling is necessary.

Effects of administration route, dietary condition, and blood glucose level on kinetics and uptake of 18F-FDG in mice.

UNLABELLED: The effects of dietary condition and blood glucose level on the kinetics and uptake of (18)F-FDG in mice were systematically investigated using intraperitoneal and tail-vein injection. METHODS: Dynamic PET was performed for 60 min on 23 isoflurane-anesthetized male C57BL/6 mice after intravenous (n = 11) or intraperitoneal (n = 12) injection of (18)F-FDG. Five and 6 mice in the intravenous and intraperitoneal groups, respectively, were kept fasting overnight (18 ± 2 h), and the others were fed ad libitum. Serial blood samples were collected from the femoral artery to measure (18)F-FDG and glucose concentrations. Image data were reconstructed using filtered backprojection with CT-based attenuation correction. The standardized uptake value (SUV) was estimated from the 45- to 60-min image. The metabolic rate of glucose (MRGlu) and (18)F-FDG uptake constant (K(i)) were derived by Patlak graphical analysis. RESULTS: In the brain, SUV and K(i) were significantly higher in fasting mice with intraperitoneal injection, but MRGlu did not differ significantly under different dietary states and administration routes. Cerebral K(i) was inversely related to elevated blood glucose levels, irrespective of administration route or dietary state. In myocardium, SUV, K(i), and MRGlu were significantly lower in fasting than in nonfasting mice for both routes of injection. Myocardial SUV and K(i) were strongly dependent on the dietary state, and K(i) did not correlate with the blood glucose level. Similar results were obtained for skeletal muscle, although the differences were not as pronounced. CONCLUSION: Intraperitoneal injection is a valid alternative route, providing pharmacokinetic data equivalent to data from tail-vein injection for small-animal (18)F-FDG PET. Cerebral K(i) varies inversely with blood glucose level, but the measured cerebral MRGlu does not correlate with blood glucose level or dietary condition. Conversely, the K(i) values of the myocardium and skeletal muscle are strongly dependent on dietary condition but not on blood glucose level. In tissue in which (18)F-FDG uptake declines with increasing blood glucose, correction for blood glucose level will make SUV a more robust outcome measure of MRGlu.

Unexpected expression pattern for glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1) in mouse tissues revealed by positron emission tomography scanning.

Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1), a GPI-anchored endothelial cell protein, binds lipoprotein lipase (LPL) and transports it into the lumen of capillaries where it hydrolyzes triglycerides in lipoproteins. GPIHBP1 is assumed to be expressed mainly within the heart, skeletal muscle, and adipose tissue, the sites where most lipolysis occurs, but the tissue pattern of GPIHBP1 expression has never been evaluated systematically. Because GPIHBP1 is found on the luminal face of capillaries, we predicted that it would be possible to define GPIHBP1 expression patterns with radiolabeled GPIHBP1-specific antibodies and positron emission tomography (PET) scanning. In Gpihbp1(-/-) mice, GPIHBP1-specific antibodies were cleared slowly from the blood, and PET imaging showed retention of the antibodies in the blood pools (heart and great vessels). In Gpihbp1(+/+) mice, the antibodies were cleared extremely rapidly from the blood and, to our surprise, were taken up mainly by lung and liver. Immunofluorescence microscopy confirmed the presence of GPIHBP1 in the capillary endothelium of both lung and liver. In most tissues with high levels of Gpihbp1 expression, Lpl expression was also high, but the lung was an exception (very high Gpihbp1 expression and extremely low Lpl expression). Despite low Lpl transcript levels, however, LPL protein was readily detectable in the lung, suggesting that some of that LPL originates elsewhere and then is captured by GPIHBP1 in the lung. In support of this concept, lung LPL levels were significantly lower in Gpihbp1(-/-) mice than in Gpihbp1(+/+) mice. In addition, Lpl(-/-) mice expressing human LPL exclusively in muscle contained high levels of human LPL in the lung.

Positron emission tomography imaging of DMBA/TPA mouse skin multi-step tumorigenesis.

Many tumor cells have elevated rates of glucose uptake that can be measured quantitatively, noninvasively and repeatedly by positron emission tomography (PET) with 2-deoxy-2-[(18)F]-fluoro-D-glucose ((18)F-FDG). Clinical imaging with (18)F-FDG PET has been used for detection and staging of primary and metastatic tumors. High-resolution microPET scanning and murine cancer models make it possible to analyze longitudinally glucose metabolism during the appearance, development and progression of individual experimental tumors. In this study, we used (18)F-FDG microPET and micro computerized tomography (microCT) to investigate glucose uptake in the DMBA/TPA chemically-induced multistage mouse skin carcinogenesis model. (18)F-FDG uptake is significantly higher in all papillomas than in surrounding skin. Elevated (18)F-FDG uptake is observed when tumors can be identified morphologically, but not before. Although (18)F-FDG uptake is high in all fully invasive, malignant skin squamous cell carcinomas, uptake in papillomas and microinvasive malignant squamous cell carcinomas is variable and does not exhibit any correlation with tumor stage.