Brain Positron Emission Tomography Imaging Research Articles

Effects of List-Mode-Based Intraframe Motion Correction in Dynamic Brain PET Imaging.

Motion is unavoidable in dynamic [18F]-MK6240 Positron Emission Tomography (PET) imaging, especially in Alzheimer's disease (AD) research requiring long scan duration. To understand how motion correction affects quantitative analysis, we investigated two approaches: II-MC, which corrects for both inter-frame and intra-frame motion, and IO-MC, which only corrects for inter-frame motion. These methods were applied to 83 scans from 34 subjects, and we calculated distribution volume ratios (DVR) using the multilinear reference tissue model with two parameters (MRTM2) in tau-rich brain regions. Most of the studies yielded similar DVR results for both II-MC and IO-MC. However, in one scan of an AD subject, the inferior temporal region showed 14% higher DVR with II-MC compared to IO-MC. This difference was reasonable given the AD diagnosis, although similar results were not observed in other regions. Although discrepancies between IO-MC and II-MC results were rare, they underscore the importance of incorporating intra-frame motion correction for more accurate and dependable PET quantitation, particularly in the context of dynamic imaging. These findings suggest that while the overall impact of intra-frame motion correction may be subtle, it can improve the reliability of longitudinal PET data, ultimately enhancing our understanding of tau protein distribution in AD pathology.

Assessing the metabolism of the olfactory circuit by use of 18F-FDG PET-CT imaging in patients suspected of suffering from Alzheimer’s disease or frontotemporal dementia

PurposeThe loss of olfactory function is known to occur in patients suffering from (behavioral variant) frontotemporal dementia ((bv)FTD) and Alzheimer’s disease (AD), although different pathophysiological mechanisms underpin this clinical symptom in both disorders. This study assessed whether brain metabolism of the olfactory circuit as assessed by positron emission tomography (PET) imaging with 2-[fluorine-18]fluoro-2-deoxy-d-glucose ([18F]-FDG) can distinguish these entities in different subsets of patients.MethodsPatients presenting with cognitive decline were included from a prospectively kept database: (1) bvFTD patients, (2) AD patients and (3) patients with logopenic primary progressive aphasia (PPA). Metabolic rates were calculated for different regions of the olfactory circuit for each subgroup and compared with a cohort of subjects with normal brain metabolism. Additionally, in patients with a logopenic PPA pattern on PET-imaging, statistical parametric mapping (SPM) analysis was performed.ResultsThe metabolism of subdivisions of the olfactory circuit as assessed by [18F]-FDG PET brain imaging to bvFTD and AD from control subjects resulted in sensitivity/specificity rates of 95/87.5% and 80/83.3%, respectively. A sensitivity/specificity rate of 100/87.5% was achieved when used to differentiate AD from bvFTD. In patients with the PPA pattern on imaging, the underlying cause (either FTD or AD) could be determined with a sensitivity/specificity rate of 88/82%. SPM analysis concurred that different regions of the olfactory circuit were affected in patients suffering from AD PPA or bvFTD PPA.ConclusionMetabolic dysfunction in the olfactory circuit is different in various neurodegenerative disorders. Further investigation of the correlations between the cerebral metabolism and the mechanisms which drive olfactory dysfunction is needed.

[11C]Metoclopramide PET can detect a seizure-induced up-regulation of cerebral P-glycoprotein in epilepsy patients

BackgroundP-glycoprotein (P-gp) is an efflux transporter which is abundantly expressed at the blood-brain barrier (BBB) and which has been implicated in the pathophysiology of various brain diseases. The radiolabelled antiemetic drug [11C]metoclopramide is a P-gp substrate for positron emission tomography (PET) imaging of P-gp function at the BBB. To assess whether [11C]metoclopramide can detect increased P-gp function in the human brain, we employed drug-resistant temporal lobe epilepsy (TLE) as a model disease with a well characterised, regional P-gp up-regulation at the BBB.MethodsEight patients with drug-resistant (DRE) TLE, 5 seizure-free patients with drug-sensitive (DSE) focal epilepsy, and 15 healthy subjects underwent brain PET imaging with [11C]metoclopramide on a fully-integrated PET/MRI system. Concurrent with PET, arterial blood sampling was performed to generate a metabolite-corrected arterial plasma input function for kinetic modelling. The choroid plexus was outmasked on the PET images to remove signal contamination from the neighbouring hippocampus. Using a brain atlas, 10 temporal lobe sub-regions were defined and analysed with a 1-tissue-2-rate constant compartmental model to estimate the rate constants for radiotracer transfer from plasma to brain (K1) and from brain to plasma (k2), and the total volume of distribution (VT = K1/k2).ResultsDRE patients but not DSE patients showed significantly higher k2 values and a trend towards lower VT values in several temporal lobe sub-regions located ipsilateral to the epileptic focus as compared to healthy subjects (k2: hippocampus: +34%, anterior temporal lobe, medial part: +28%, superior temporal gyrus, posterior part: +21%).Conclusions[11C]Metoclopramide PET can detect a seizure-induced P-gp up-regulation in the epileptic brain. The efflux rate constant k2 seems to be the most sensitive parameter to measure increased P-gp function with [11C]metoclopramide. Our study provides evidence that disease-induced alterations in P-gp expression at the BBB can lead to changes in the distribution of a central nervous system-active drug to the human brain, which could affect the efficacy and/or safety of drugs. [11C]Metoclopramide PET may be used to assess or predict the contribution of increased P-gp function to drug resistance and disease pathophysiology in various brain diseases.Trial registrationEudraCT 2019-003137-42. Registered 28 February 2020.

High-resolution motion compensation for brain PET imaging using real-time electromagnetic motion tracking.

Substantial improvements in spatial resolution in brain positron emission tomography (PET) scanners have greatly reduced partial volume effect, making head movement the main source of image blur. To achieve high-resolution PET neuroimaging, precise real-time estimation of both head position and orientation is essential for accurate motion compensation. A high-resolution electromagnetic motion tracking (EMMT) system with an event-by-event motion correction is developed for PET-CTscanners. EMMT is comprised of a source, an array of sensors, and a readout electronic unit (REU). The source acts as a transmitter and emits an EM dipole field. It is placed in close proximity to the sensor array and detects changes in EM flux density due to sensor movement. The REU digitizes signals from each sensor and captures precise rotational and translational movements in real time. Tracked motion in the EMMT coordinate system is synchronized with the PET list-mode data and transformed into the scanner coordinate system by locating paired positions in both systems. The optimal rigid motion is estimated using singular value decomposition. The rigid motion and depth-of-interaction (DOI) parallax effect are corrected by event-by-event rebinning of mispositioned lines-of-response (LORs). We integrated the EMMT with our recently developed ultra-high resolution Prism-PET prototype brain scanner and a commercial Siemens Biograph mCT PET-CT scanner. We assessed the imaging performance of the Prism-PET/EMMT system using multi-frame motion of point sources and phantoms. The mCT/EMMT system was validated using a set of point sources attached to both a mannequin head and a human volunteer, for simulating multiframe and continuous motions, respectively. Additionally, a human subject for [18F]MK6240 PET imaging wasincluded. The tracking accuracy of the Prism-PET/EMMT system was quantified as a root-mean-square (RMS) error of 0.49 for 100 axial rotations, and an RMS error of 0.15 mm for 100 mm translations.The percent difference (%diff) in average full width at half maximum (FWHM) of point source between motion-corrected and static images, within a motion range of and 10 mm from the center of the scanner's field-of-view (FOV), was 3.9%. The measured recovery coefficients of the 2.5-mm diameter sphere in the activity-filled partial volume correction phantom were 23.9%, 70.8%, and 74.0% for the phantom with multi-frame motion, with motion and motion compensation, and without motion, respectively. In the mCT/EMMT system, the %diff in average FWHM of point sources between motion-corrected and static images, within a motion range of and 10 mm from the center of the FOV, was 14%. Applying motion correction to the [18F]MK6240 PET imaging reduced the motion-induced spill-in artifact in the lateral ventricle region, lowering its standardized uptake value ratio (SUVR) from 0.70 to 0.34. The proposed EMMT system is a cost-effective, high frame-rate, and none-line-of-sight alternative to infrared camera-based tracking systems and is capable of achieving high rotational and translational tracking accuracies for mitigating motion-induced blur in high-resolution brain dedicated PETscanners.

Phantom test procedures for a new neuro-oncological amino acid PET tracer: [18F]fluciclovine.

Amino acid positron emission tomography (PET) examinations using anti-1-amino-3-[18F]-fluorocyclobutane-1-carboxylic acid ([18F]FACBC) were allowed for routine clinical use in July 2024. However, phantom test procedures for [18F]FACBC reconstruction parameters have not yet been established. The present study aimed to establish new phantom test procedures for [18F]FACBC brain PET imaging to determine optimal reconstruction parameters. Background (BG) activity as well as hot sphere and target-to-background ratios (TBRs) of [18F]FACBC were estimated based on brain activity and tumor-to-normal tissue ratios (TNR) in a Japanese clinical trial of [18F]FACBC. Phantom experiments proceeded under [18F]FACBC or L-[methyl-11C]-methionine ([11C]MET) conditions. The number of iterations and the Gaussian filter parameters were determined from the reconstruction parameters %contrastmean and coefficients of variation (CVs) in ordered subset expectation maximization (OSEM) and time-of-flight (TOF) with or without point-spread-function (PSF) correction. The amounts of activity in the hot spheres and BG were 1.1 and 5.5kBq/mL, respectively, and the TBR was 5.0 at the start of acquisition. The %contrastmean of all hot spheres was higher with [18F]FACBC than [11C]MET, and %contrastmean converged between 4 and 6 iterations in hot spheres with diameters < 10mm. We used four iterations for OSEM + TOF and five for OSEM + TOF + PSF correction for [18F]FACBC and [11C]MET images. The CV was higher for [18F]FACBC than [11C]MET. The optimal sizes of Gaussian filters for OSEM + TOF and OSEM + TOF + PSF correction of image reconstruction were 5mm for [18F]FACBC, and 4 and 3mm, respectively, for [11C]MET images. We estimated phantom activity and TBR based on brain activity in a Japanese clinical trial and established new phantom test procedures for [18F]FACBC. We recommend that the optimal reconstruction parameters for [18F]FACBC should be set to the same number of iterations as [11C]MET and that the FWHM of Gaussian filter should have a few mm higher than [11C]MET to reduce image noise from brain normal tissue.

Microglia-mediated neuroimmune suppression in PTSD is associated with anhedonia

Dynamic brain immune function in individuals with posttraumatic stress disorder is rarely studied, despite evidence of peripheral immune dysfunction. Positron emission tomography brain imaging using the radiotracer [11C]PBR28 was used to measure the 18-kDa translocator protein (TSPO), a microglial marker, at baseline and 3 h after administration of lipopolysaccharide (LPS), a potent immune activator. Data were acquired in 15 individuals with PTSD and 15 age-matched controls. The PTSD group exhibited a significantly lower magnitude LPS-induced increase in TSPO availability in an a priori prefrontal-limbic circuit compared to controls. Greater anhedonic symptoms in the PTSD group were associated with a more suppressed neuroimmune response. In addition, while a reduced granulocyte-macrophage colony-stimulating factor response to LPS was observed in the PTSD group, other measured cytokine responses and self-reported sickness symptoms did not differ between groups; these findings highlight group differences in central-peripheral immune system relationships. The results of this study provide evidence of a suppressed microglia-mediated neuroimmune response to a direct immune system insult in individuals with PTSD that is associated with the severity of symptoms. They also provide further support to an emerging literature challenging traditional concepts of microglial and immune function in psychiatric disease.

The Effect of Therapeutic Hypothermia on Ischemic Brain Injury in a Rat Model of Cardiac Arrest: An Assessment Using 18F-FDG PET.

Therapeutic hypothermia (TH) is widely acknowledged as one of the interventions for preventing hypoxic ischemic brain injury in comatose patients following cardiac arrest (CA). Despite its recognized efficacy, recent debates have questioned its effectiveness. This preclinical study evaluated the impact of TH on brain glucose metabolism, utilizing fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) in a rat model of CA. Asphyxia CA was induced in Sprague-Dawley rats using vecuronium. Brain PET images using 18F-FDG were obtained from 21 CA rats, who were randomized to receive either TH or no intervention. Of these, 9 rats in the TH group received hypothermia under general anesthesia and mechanical ventilation for eight hours, while the remaining 12 rats in the non-TH group were observed without intervention. We conducted regional and voxel-based analyses of standardized uptake values relative to the pons (SUVRpons) to compare the two groups. Survival rates were identical in both the TH and non-TH groups (67%). There was no discernible difference in the SUVRpons across the brain cortical regions between the groups. However, in a subgroup analysis of the rats that did not survive (n = 7), those in the TH group (n = 3) displayed significantly higher SUVRpons values across most cortical regions compared to those in the non-TH group (n = 4), with statistical significance after false-discovery rate correction (p < 0.05). The enhancement in SUVRpons due to TH intervention was only observed in the cortical regions of rats with severe encephalopathy that subsequently died. These findings suggest that the beneficial effects of TH on brain glucose metabolism in this asphyxia CA model may be confined to cases of severe ischemic encephalopathy.

Enhancing Feature Selection in MCI Diagnosis using FDG-PET Images: Leveraging Multiple Simple Autoencoder Architectures

Alzheimer’s Disease (AD) is the most common type of neurodegenerative brain disease in elderly people. Early diagnosis of AD is crucial for providing suitable care. Positron Emission Tomography (PET) images and machine learning can be used to support this purpose. In this paper, we present a method for ranking the effectiveness of brain regions of interest (ROIs) to distinguish between stable mild cognitive impairment (sMCI) from progressive mild cognitive impairment (pMCI) in brain PET images based on AutoEncoder (AE). Experiments on the ADNI dataset show that our proposed method significantly improves classifier performance when compared to other popular feature ranking methods such as Fisher score, t-score, and LASSO. Our results suggest that instead of focusing on designing a complex AE structure, we can also use simple-but-multiple AEs for feature ranking. The proposed method could be easily applied to any image dataset where a feature selection is needed.

Improving diagnostic precision in amyloid brain PET imaging through data-driven motion correction

BackgroundHead motion during brain positron emission tomography (PET)/computed tomography (CT) imaging degrades image quality, resulting in reduced reading accuracy. We evaluated the performance of a head motion correction algorithm using 18F-flutemetamol (FMM) brain PET/CT images.MethodsFMM brain PET/CT images were retrospectively included, and PET images were reconstructed using a motion correction algorithm: (1) motion estimation through 3D time-domain signal analysis, signal smoothing, and calculation of motion-free intervals using a Merging Adjacent Clustering method; (2) estimation of 3D motion transformations using the Summing Tree Structural algorithm; and (3) calculation of the final motion-corrected images using the 3D motion transformations during the iterative reconstruction process. All conventional and motion-corrected PET images were visually reviewed by two readers. Image quality was evaluated using a 3-point scale, and the presence of amyloid deposition was interpreted as negative, positive, or equivocal. For quantitative analysis, we calculated the uptake ratio (UR) of 5 specific brain regions, with the cerebellar cortex as a reference region. The results of the conventional and motion-corrected PET images were statistically compared.ResultsIn total, 108 sets of FMM brain PET images from 108 patients (34 men and 74 women; median age, 78 years) were included. After motion correction, image quality significantly improved (p < 0.001), and there were no images of poor quality. In the visual analysis of amyloid deposition, higher interobserver agreements were observed in motion-corrected PET images for all specific regions. In the quantitative analysis, the UR difference between the conventional and motion-corrected PET images was significantly higher in the group with head motion than in the group without head motion (p = 0.016).ConclusionsThe motion correction algorithm provided better image quality and higher interobserver agreement. Therefore, we suggest that this algorithm be adopted as a routine post-processing protocol in amyloid brain PET/CT imaging and applied to brain PET scans with other radiotracers.

Kinetic modeling of the monoamine oxidase-B radioligand [18F]SMBT-1 in human brain with positron emission tomography

This paper describes pharmacokinetic analyses of the monoamine-oxidase-B (MAO-B) radiotracer [18F](S)-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline ([18F]SMBT-1) for positron emission tomography (PET) brain imaging. Brain MAO-B expression is widespread, predominantly within astrocytes. Reactive astrogliosis in response to neurodegenerative disease pathology is associated with MAO-B overexpression. Fourteen elderly subjects (8 control, 5 mild cognitive impairment, 1 Alzheimer’s disease) with amyloid ([11C]PiB) and tau ([18F]flortaucipir) imaging assessments underwent dynamic [18F]SMBT-1 PET imaging with arterial input function determination. [18F]SMBT-1 showed high brain uptake and a retention pattern consistent with the known MAO-B distribution. A two-tissue compartment (2TC) model where the K1/k2 ratio was fixed to a whole brain value best described [18F]SMBT-1 kinetics. The 2TC total volume of distribution (VT) was well identified and highly correlated (r2∼0.8) with post-mortem MAO-B indices. Cerebellar grey matter (CGM) showed the lowest mean VT of any region and is considered the optimal pseudo-reference region. Simplified analysis methods including reference tissue models, non-compartmental models, and standard uptake value ratios (SUVR) agreed with 2TC outcomes (r2 > 0.9) but with varying bias. We found the CGM-normalized 70–90 min SUVR to be highly correlated (r2 = 0.93) with the 2TC distribution volume ratio (DVR) with acceptable bias (∼10%), representing a practical alternative for [18F]SMBT-1 analyses.

Impaired Self-Awareness in Parkinson's and Huntington's Diseases: A Literature Review of Neuroimaging Correlates.

Little is known about the brain correlates of anosognosia or unawareness of disease in Parkinson's Disease (PD) and Huntington's Disease (HD). The presence of unawareness or impaired self-awareness (ISA) of illness has profound implications for patients and their caregivers; therefore, studying awareness and its brain correlates should be considered a key step towards developing effective recognition and management of this symptom as it offers a window into the mechanism of self-awareness and consciousness as critical components of the human cognition. We reviewed research studies adopting MRI or other in vivo neuroimaging technique to assess brain structural and/or functional correlates of unawareness in PD and HD across different cognitive and motor domains. Studies adopting task or resting-state functional magnetic resonance imaging, and/or 18-F fluorodeoxyglucose positron emission tomography brain imaging and/or magnetic resonance imaging structural measures were considered. Only six studies investigating neuroimaging features of unawareness in PD and two in HD were identified; there was great heterogeneity in the clinical characteristics of the study participants, domain of unawareness investigated, method of unawareness assessment, and neuroimaging technique used. Nevertheless, some data converge in identifying regions of the salience and frontoparietal networks to be associated with unawareness in PD patients. In HD, the few data are affected by the variability in the severity of motor symptoms. Further studies are needed to better understand the mechanisms and brain correlates of unawareness in PD and HD; in addition, the use of dopaminergic medications should be carefully considered.

Imaging a putative marker of brain cortisol regulation in alcohol use disorder

BackgroundStress is a potent activator of the hypothalamic-pituitary-adrenal (HPA) axis, initiating the release of glucocorticoid hormones, such as cortisol. Alcohol consumption can lead to HPA axis dysfunction, including altered cortisol levels. Until recently, research has only been able to examine peripheral cortisol associated with alcohol use disorder (AUD) in humans. We used positron emission tomography (PET) brain imaging with the radiotracer [18F]AS2471907 to measure 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a cortisol-regenerating enzyme, in people with AUD compared to healthy controls. MethodsWe imaged 9 individuals with moderate to severe AUD (5 men, 4 women; mean age = 38 years) and 12 healthy controls (8 men, 4 women; mean age = 29 years). Participants received 93.5 ± 15.6 MBq of the 11β-HSD1 inhibitor radiotracer [18F]AS2471907 as a bolus injection and were imaged for 150–180 min on the High-Resolution Research Tomograph. 11β-HSD1 availability was quantified by [18F]AS2471907 volume of distribution (VT; mL/cm3). A priori regions of interest included amygdala, anterior cingulate cortex (ACC), hippocampus, ventromedial PFC (vmPFC) and caudate. ResultsIndividuals with AUD consumed 52.4 drinks/week with 5.8 drinking days/week. Healthy controls consumed 2.8 drinks/week with 1.3 drinking days/week. Preliminary findings suggest that [18F]AS2471907 VT was higher in amygdala, ACC, hippocampus, vmPFC, and caudate of those with AUD compared to healthy controls (p < 0.05). In AUD, vmPFC [18F]AS2471907 VT was associated with drinks per week (r = 0.81, p = 0.01) and quantity per drinking episode (r = 0.75, p = 0.02). ConclusionsThis is the first in vivo examination of 11β-HSD1 availability in individuals with AUD. Our data suggest higher brain availability of the cortisol-regenerating enzyme 11β-HSD1 in people with AUD (vs. controls), and that higher vmPFC 11β-HSD1 availability is related to greater alcohol consumption. Thus, in addition to the literature suggesting that people with AUD have elevated peripheral cortisol, our findings suggest there may also be heightened central HPA activity. These findings set the foundation for future hypotheses on mechanisms related to HPA axis function in this population.

Development and evaluation of a new high-TOF-resolution all-digital brain PET system

Objective. Time-of-flight (TOF) capability and high sensitivity are essential for brain-dedicated positron emission tomography (PET) imaging, as they improve the contrast and the signal-to-noise ratio (SNR) enabling a precise localization of functional mechanisms in the different brain regions. Approach. We present a new brain PET system with transverse and axial field-of-view (FOV) of 320 mm and 255 mm, respectively. The system head is an array of 6 × 6 detection elements, each consisting of a 3.9 × 3.9 × 20 mm3 lutetium–yttrium oxyorthosilicate crystal coupled with a 3.93 × 3.93 mm2 SiPM. The SiPMs analog signals are individually digitized using the multi-voltage threshold (MVT) technology, employing a 1:1:1 coupling configuration. Main results. The brain PET system exhibits a TOF resolution of 249 ps at 5.3 kBq ml−1, an average sensitivity of 22.1 cps kBq−1, and a noise equivalent count rate (NECR) peak of 150.9 kcps at 8.36 kBq ml−1. Furthermore, the mini-Derenzo phantom study demonstrated the system’s ability to distinguish rods with a diameter of 2.0 mm. Moreover, incorporating the TOF reconstruction algorithm in an image quality phantom study optimizes the background variability, resulting in reductions ranging from 44% (37 mm) to 75% (10 mm) with comparable contrast. In the human brain imaging study, the SNR improved by a factor of 1.7 with the inclusion of TOF, increasing from 27.07 to 46.05. Time-dynamic human brain imaging was performed, showing the distinctive traits of cortex and thalamus uptake, as well as of the arterial and venous flow with 2 s per time frame. Significance. The system exhibited a good TOF capability, which is coupled with the high sensitivity and count rate performance based on the MVT digital sampling technique. The developed TOF-enabled brain PET system opens the possibility of precise kinetic brain PET imaging, towards new quantitative predictive brain diagnostics.

Challenges and innovations in brain PET analysis of neurodegenerative disorders: a mini-review on partial volume effects, small brain region studies, and reference region selection.

Positron Emission Tomography (PET) brain imaging is increasingly utilized in clinical and research settings due to its unique ability to study biological processes and subtle changes in living subjects. However, PET imaging is not without its limitations. Currently, bias introduced by partial volume effect (PVE) and poor signal-to-noise ratios of some radiotracers can hamper accurate quantification. Technological advancements like ultra-high-resolution scanners and improvements in radiochemistry are on the horizon to address these challenges. This will enable the study of smaller brain regions and may require more sophisticated methods (e.g., data-driven approaches like unsupervised clustering) for reference region selection and to improve quantification accuracy. This review delves into some of these critical aspects of PET molecular imaging and offers suggested strategies for improvement. This will be illustrated by showing examples for dopaminergic and cholinergic nerve terminal ligands.

Synthesis and evaluation of a novel PET ligand, a GSK’963 analog, aiming at autoradiography and imaging of the receptor interacting protein kinase 1 in the brain

BackgroundReceptor interacting protein kinase 1 (RIPK1) is a serine/threonine kinase, which regulates programmed cell death and inflammation. Recently, the involvement of RIPK1 in the pathophysiology of Alzheimer’s disease (AD) has been reported; RIPK1 is involved in microglia’s phenotypic transition to their dysfunctional states, and it is highly expressed in the neurons and microglia in the postmortem brains in AD patients. They prompt neurodegeneration leading to accumulations of pathological proteins in AD. Therefore, regulation of RIPK1 could be a potential therapeutic target for the treatment of AD, and in vivo imaging of RIPK1 may become a useful modality in studies of drug discovery and pathophysiology of AD. The purpose of this study was to develop a suitable radioligand for positron emission tomography (PET) imaging of RIPK1.Results(S)-2,2-dimethyl-1-(5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)propan-1-one (GSK’963) has a high affinity, selectivity for RIPK1, and favorable physiochemical properties based on its chemical structure. In this study, since 11C-labeling (half-life: 20.4 min) GSK’963 retaining its structure requiring the Grignard reaction of tert-butylmagnesium halides and [11C]carbon dioxide was anticipated to give a low yield, we decided instead to 11C-label a GSK’963 analog ((S)-2,2-dimethyl-1-(5-(m-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)propan-1-one, GG502), which has a high RIPK1 inhibitory activity equivalent to that of the original compound GSK’963. Thus, we successfully 11C-labeled GG502 using a Pd-mediated cross-coupling reaction in favorable yields (3.6 ± 1.9%) and radiochemical purities (> 96%), and molar activity (47–115 GBq/μmol). On autoradiography, radioactivity accumulation was observed for [11C]GG502 and decreased by non-radioactive GG502 in the mouse spleen and human brain, indicating the possibility of specific binding of this ligand to RIPK1. On brain PET imaging in a rhesus monkey, [11C]GG502 showed a good brain permeability (peak standardized uptake value (SUV) ~3.0), although there was no clear evidence of specific binding of [11C]GG502. On brain PET imaging in acute inflammation model rats, [11C]GG502 also showed a good brain permeability, and no significant increased uptake was observed in the lipopolysaccharide-treated side of striatum. On metabolite analysis in rats at 30 min after administration of [11C]GG502, ~55% and ~10% of radioactivity was from unmetabolized [11C]GG502 in the brain and the plasma, respectively.ConclusionsWe synthesized and evaluated a 11C-labeled PET ligand based on the methylated analog of GSK’963 for imaging of RIPK1 in the brain. Although in autoradiography of the resulting [11C]GG502 indicated the possibility of specific binding, the actual PET imaging failed to detect any evidence of specific binding to RIPK1 despite its good brain permeability. Further development of radioligands with a higher binding affinity for RIPK1 in vivo and more stable metabolite profiles compared with the current compound may be required.

Forecasting the Pharmacokinetics With Limited Early Frames in Dynamic Brain PET Imaging Using Neural Ordinary Differential Equation

In dynamic brain positron emission tomography (PET) studies, acquiring a time series of images, typically lasting more than an hour, is necessary to derive pharmacokinetic parameters. Analytically, these parameters are estimated by establishing kinetic models such as compartment models that consist of sets of ordinary differential equations (ODE), and by fitting the sparse time-activity curve (TAC) of the tracer. Yet, these models are simplified approximations of highly complex underlying processes, and sufficient samples of TAC are required throughout the entire acquisition, which is not only impractical but also hindered by patient involuntary motion and intrinsic noise. Therefore, recovering samples in missing timeframes is often required, which, in practice, is achieved by interpolation or extrapolation. Here, we introduce a novel deep-learning-based method that utilizes neural ODE (N-ODE) to predict TAC in the extended timeframes by mimicking analytical method in a data-driven manner. By training N-ODE to solve and fit sets of ODE such that the solution replicates the observed TAC, the N-ODE converges to the functional shapes that best describe the underlying pharmacokinetic processes. We customized N-ODE to predict the full-dynamic images (12 frames, 60min), hence pharmacokinetic parameters, given limited early-frame images (7 to 9 frames, 20 to 30min). For proof of concept, the proposed N-ODE was applied to simulated and clinical 18F-PI-2620 brain PET. We demonstrated that the proposed N-ODE delivered promising performance, indicated by bias, variance, and mean absolute error as well as pharmacokinetic parameters such as rate constants, standardized uptake value ratio (SUVr), and binding potential (BPND).

Neurocognitive Profile and 18 F-Fluorodeoxyglucose Positron Emission Tomography Brain Imaging Correlation in Children with Electrical Status Epilepticus during Sleep.

Objective Electrical status epilepticus in sleep (ESES) is defined by near-continuous epileptiform discharges during sleep along with cognitive, behavioral, and/or imaging abnormalities. We studied the neurocognitive profile and their correlation with 18 F fluorodeoxyglucose positron emission tomography (FDG PET) brain abnormalities in children with ESES. Methods Fourteen children with ESES with normal magnetic resonance imaging (MRI) from March to December 2019 were included. The intelligence quotient (IQ) and child behavior checklist (CBCL) scores were estimated using validated scales, and FDG PET brain was done at the same point of time to look for cerebral metabolic defects which was compared with a control group. Results Fourteen patients with a mean age of 8.2 ± 2.7 years were analyzed. The average duration of epilepsy was 6 ± 2.8 years. The mean IQ was 72.4 ± 18.2 and mean CBCL score was 37.3 ± 11.8. There was negative correlation between IQ and CBCL ( r = -0.55, p < 0.001). The duration of epilepsy also showed negative correlation with IQ ( r = -4.75, p < 0.001). FDG PET scan showed predominant thalamic hypometabolism in 12 of 14 patients (85.7%) on visual analysis with multiple other hypometabolic cortical and subcortical regions in the brain. The quantitative analysis showed significant difference in metabolism of basal ganglion when compared with control group. The total number of hypometabolic regions seen in the brain showed moderate positive correlation with CBCL score but no significant correlation with the IQ of cases. Conclusion This study demonstrates functional impairment of cerebral cortical, basal ganglia, and thalamic hypometabolism in a cohort of ESES patients with normal structural MRI brain study. There was a moderate correlation of extent and pattern of cerebral hypometabolism with the neuropsychological status of the child and duration of epilepsy.

Permutation-based inference for function-on-scalar regression with an application in PET brain imaging

The density of various proteins throughout the human brain can be studied through the use of positron emission tomography (PET) imaging. We report here on data from a study of serotonin transporter (5-HTT) binding. While PET imaging data analysis is most commonly performed on data that are aggregated into several discrete a priori regions of interest, in this study, primary interest is on measures of 5-HTT binding potential that are made at many locations along a continuous anatomically defined tract, one that was chosen to follow serotonergic axons. Our goal is to characterise the binding patterns along this tract and also to determine how such patterns differ between control subjects and depressed patients. Due to the nature of our data, we utilise function-on-scalar regression modelling to make optimal use of our data. Inference on both main effects (position along the tract; diagnostic group) and their interactions are made using permutation testing strategies that do not require distributional assumptions. Also, to investigate the question of homogeneity we implement a permutation testing strategy, which adapts a ‘block bootstrapping’ approach from time series analysis to the functional data setting.

MULTI-TASK DEEP LEARNING AND UNCERTAINTY ESTIMATION FOR PET HEAD MOTION CORRECTION.

Head motion occurring during brain positron emission tomography images acquisition leads to a decrease in image quality and induces quantification errors. We have previously introduced a Deep Learning Head Motion Correction (DL-HMC) method based on supervised learning of gold-standard Polaris Vicra motion tracking device and showed the potential of this method. In this study, we upgrade our network to a multi-task architecture in order to include image appearance prediction in the learning process. This multi-task Deep Learning Head Motion Correction (mtDL-HMC) model was trained on 21 subjects and showed enhanced motion prediction performance compared to our previous DL-HMC method on both quantitative and qualitative results for 5 testing subjects. We also evaluate the trustworthiness of network predictions by performing Monte Carlo Dropout at inference on testing subjects. We discard the data associated with a great motion prediction uncertainty and show that this does not harm the quality of reconstructed images, and can even improve it.

Cholinergic system adaptations are associated with cognitive function in people recently abstinent from smoking: a (-)-[18F]flubatine PET study.

The cholinergic system is a critical mediator of cognition in animals. People who smoke cigarettes exhibit cognitive deficits, especially during quit attempts. Few studies jointly examine the cholinergic system and cognition in people while trying to quit smoking. We used positron emission tomography (PET) brain imaging with the β2-subunit containing nicotinic acetylcholine receptor (β2*-nAChR) partial agonist radioligand (-)-[18F]flubatine and the acetylcholinesterase inhibitor physostigmine to jointly examine the cholinergic system, smoking status, and cognition. (-)-[18F]Flubatine scans and cognitive data were acquired from twenty people who recently stopped smoking cigarettes (aged 38 ± 11 years; 6 female, 14 male; abstinent 7 ± 1 days) and 27 people who never smoked cigarettes (aged 29 ± 8 years; 11 female, 16 male). A subset of fifteen recently abstinent smokers and 21 never smokers received a mid-scan physostigmine challenge to increase acetylcholine levels. Regional volume of distribution (VT) was estimated with equilibrium analysis at "baseline" and post-physostigmine. Participants completed a cognitive battery prior to (-)-[18F]flubatine injection and physostigmine administration assessing executive function (Groton Maze Learning test), verbal learning (International Shopping List test), and working memory (One Back test). Physostigmine significantly decreased cortical (-)-[18F]flubatine VT, consistent with increased cortical acetylcholine levels reducing the number of β2*-nAChR sites available for (-)-[18F]flubatine binding, at comparable magnitudes across groups (p values < 0.05). A larger magnitude of physostigmine-induced decrease in (-)-[18F]flubatine VT was significantly associated with worse executive function in people who recently stopped smoking (p values < 0.05). These findings underscore the role of the cholinergic system in early smoking cessation and highlight the importance of neuroscience-informed treatment strategies.