Positron Emission Tomography Studies Research Articles

Brain Abscess Causes Brain Damage With Long-Lasting Focal Cerebral Hypoactivity that Correlates With Abscess Size: A Cross-Sectional 18F-Fluoro-Deoxyglucose Positron Emission Tomography Study

BACKGROUND AND OBJECTIVES: Bacterial brain abscesses may have long-term clinical consequences, eg, mental fatigue or epilepsy, but long-term structural consequences to the brain remain underexplored. We asked if brain abscesses damage brain activity long term, if the extent of such damage depends on the size of the abscess, and if the abscess capsule, which is often left in place during neurosurgery, remains a site of inflammation, which could explain long-lasting symptoms in patients with brain abscess. METHODS: 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT), electroencephalography, and MRI were performed 2 days to 9 years after neurosurgery for bacterial brain abscess. RESULTS: FDG-PET/CT revealed hypometabolism in the neocortex or cerebellum overlying the previous bacterial abscess in 38 of 40 patients. The larger the abscess, the greater was the extent of the subsequent hypometabolism (r = 0.63; p = 3 × 10−5). In 9 patients, the extent of subsequent hypometabolism seemed to coincide with the extent of peri-abscess edema in the acute phase. Follow-up MRI after ≥1 year in 9 patients showed focal tissue loss and gliosis. In 13 patients with abnormal electroencephalography recordings, abnormalities extended beyond the cerebral lobe affected by the abscess, indicating damage to wider brain networks. The abscess capsule had an FDG signal indicating inflammation only during the first week after neurosurgical pus drainage. CONCLUSION: The bigger a brain abscess is allowed to grow, the more extensive is the long-term focal reduction in brain activity. This finding emphasizes the need for rapid neurosurgical intervention. The abscess capsule does not display long-lasting inflammation and probably does not explain long-term symptoms after brain abscess.

NIMG-24. PRECISION GLIOBLASTOMA MANAGEMENT USING MET AND FMISO PET SCANS

Abstract OBJECTIVE Positron Emission Tomography (PET) may be useful in diagnosing glioblastoma, determining resection areas, and evaluating therapeutic efficacy. This study evaluated the usefulness of PET scans using 11C-Methionine (MET) to assess amino acid metabolism and 18F-Fluoromisonidazole (FMISO) to assess hypoxic regions in glioblastoma treatment. METHODS Thirty glioblastoma patients who underwent MET and FMISO PET studies from July 2013 to March 2024 were included. Patients underwent the Stupp regimen post-tumor resection and were treated with temozolomide (TMZ) and bevacizumab (Bev) upon recurrence. PET scans were performed before and after two courses of Bev treatment. Changes in tumor to normal ratio (TNR) for MET, tumor to blood ratio (TBR) for FMISO, and metabolic tumor volume (MTV) for both MET and FMISO were evaluated. Progression-free survival (PFS) and overall survival (OS) were compared based on the rate of change in MTV for MET and FMISO. RESULTS The residual volumes (contrast-enhanced MRI, MET, and FMISO) with a MET removal rate of >90% were 0.08 ml, 0.1 ml, and 0.08 ml, respectively. For FMISO removal rates of >90%, residual volumes were 0.36 ml, 1.54 ml, and 0.05 ml, respectively. Groups with a decreased rate of change in MET MTV had significantly better outcomes: PFS (months) 10.7 vs. 2.8 (p=0.19) and OS (months) 18.6 vs. 4.9 (p=0.09). In the FMISO groups, decreased TBR change rates correlated with better outcomes: PFS (months) 16.6 vs. 2.5 (p<0.01) and OS (months) 22.8 vs. 4.9 (p<0.01). MTV change rates also showed significant differences in outcomes: PFS (months) 10.5 vs. 3.7 (p=0.76) and OS (months) 14.9 vs. 7.0 (p=0.87). CONCLUSION Higher MET removal rates correlate with fewer contrast-enhanced MRI and FMISO accumulation areas, suggesting MET as a reliable tumor removal indicator. Both MET and FMISO PET scans are valuable in determining glioblastoma treatment response.

Increased dopamine D2/D3 receptor and serotonin transporter availability in male rats after spontaneous remission from repeated social defeat-induced depression; a PET study in rats

Most pharmacological treatments for depression target monoamine transporters and about 50 % of treated patients attain symptomatic remission. Once remission is attained, it is hard to distinguish the changes on brain monoaminergic transmission induced by the antidepressants, from those associated to remission per se. In this study, we aimed at studying the brain of spontaneously remitted rats from repeated social defeat (RSD)-induced depression in terms of dopamine D2/D3 receptor and serotonin transporter (SERT) availability, showing absence of depressive symptoms 2 weeks after RSD. We combined behavioral tests and positron emission tomography (PET) with [11C]raclopride and [11C]DASB to explore the changes in dopamine D2/D3 receptor and serotonin transporter (SERT) availability, respectively. Male rats submitted to RSD showed increased peripheral corticosterone levels, decreased body weight and anhedonia, as measured with the sucrose preference test, 1 day after RSD, confirming depressive-like symptoms. These depressive-like symptoms were no longer present 2 weeks after RSD. Rats that recovered from depressive-like symptoms showed decreased D2/D3 receptor binding in the caudate putamen and increased SERT availability in the brainstem, insular cortex, midbrain and thalamus, compared to control non-stressed animals. Our study shows that remission of depressive-like symptoms does not just “normalize” monoaminergic transmission, as changes in dopaminergic and serotonergic neurotransmission linger in several brain regions even after depressive-like symptoms have already resolved. These results provide new insights into the brain changes associated to remission in the RSD-induced depression model in rats.

“Neuroinflammation”: does it have a role in chronic pain? Evidence from human imaging

Abstract Despite hundreds of studies demonstrating the involvement of neuron-glia-immune interactions in the establishment and/or maintenance of persistent pain behaviors in animals, the role (or even occurrence) of so-called “neuroinflammation” in human pain has been an object of contention for decades. Here, I present the results of multiple positron emission tomography (PET) studies measuring the levels of the 18 kDa translocator protein (TSPO), a putative neuroimmune marker, in individuals with various pain conditions. Overall, these studies suggest that brain TSPO PET signal: (1) is elevated, compared to healthy volunteers, in individuals with chronic low back pain (with additional elevations in spinal cord and neuroforamina), fibromyalgia, migraine and other conditions characterized by persistent pain; (2) has a spatial distribution exhibiting a degree of disorder specificity; (3) is parametrically linked to pain characteristics or comorbid symptoms (eg, nociplastic pain, fatigue, depression), as well as measures of brain function (ie, functional connectivity), in a regionally-specific manner. In this narrative, I also discuss important caveats to consider in the interpretation of this work (eg, regarding the cellular source of the signal and the complexities inherent in its acquisition and analysis). While the biological and clinical significance of these findings awaits further work, this emerging preclinical literature supports a role of neuron-glia-immune interactions as possible pathophysiological underpinnings of human chronic pain. Gaining a deeper understanding of the role of neuroimmune function in human pain would likely have important practical implications, possibly paving the way for novel interventions.

Brain drug delivery from the nasal olfactory region is enhanced using lauroylcholine chloride: An estimation using in vivo PET imaging

IntroductionIntranasal (IN) administration, often referred to as nose-to-brain (N2B) drug delivery, is an attractive approach for delivering drugs to the central nervous system. However, the efficacy of this method is limited because of the small size of the nasal olfactory region, which limits the drug dosage. Using permeation enhancers could improve drug delivery from this region to the brain, though their effects are not fully understood. We therefore investigated the effects of co-administration of permeation enhancers on N2B drug delivery of a model drug domperidone, a peripherally acting dopamine D2 receptor (D2R) blocker. MethodsWe conducted in vitro permeability assays to evaluate the effects of sodium lauryl sulfate (SLS), a classical permeation enhancer, and lauroylcholine chloride (LCC) on domperidone permeation in human nasal mucosa-derived cells. We also used the D2R ligand [11C]raclopride to assess the in vivo effects of LCC on domperidone delivery in the rat brain using a positron emission tomography (PET) competition paradigm. In comparative PET experiments, we tested the effects of intravenously administered domperidone without LCC co-administration. ResultsLCC effectively improved nasal mucosal permeation of domperidone in vitro compared to SLS. In rat IN administration experiments, striatal [11C]raclopride uptake was significantly decreased by the addition of LCC to domperidone. On the other hand, intravenously administered domperidone with or without intranasally administered LCC did not decrease [11C]raclopride brain uptake, suggesting a lesser influence of peripheral domperidone on [11C]raclopride brain uptake. PET studies showed that striatal D2R occupancy of domperidone was increased 2.4-fold by co-administration of LCC. ConclusionLCC effectively enhances the domperidone delivery from the rat olfactory region to the brain, probably not via a circulating blood. The combination of permeation enhancers and olfactory region-selective drug administration could be effective for N2B drug delivery.

Quantum Entanglement Filtering: A PET feasibility study in imaging dual-positron and prompt gamma emission via Monte Carlo simulation.

In this article, we investigate quantum entanglement (QE) filtering to address the challenges in multi-isotope positron emission tomography (PET) or in PET studies utilizing radiotracers with dual- positron and prompt gamma emissions. Via GATE simulation, we demonstrate the efficacy of QE filtering using a one-of-a-kind cadmium zinc telluride (CZT) PET system - establishing its viability as a multimodal scanner and ability to perform QE filtering. We show the high Compton scattering probability in this CZT-based scanner with 44.2% of gammas undergoing a single scatter prior to absorption. Additionally, the overall system sensitivity as a standard PET scanner (11.29%), QE-PET scanner (6.81%), and Compton Camera (11.29%) is quantified. Further, we find a 23% decrease in the double Compton scatter (DCSc) frequency needed for QE filtering for each mm decrease in crystal resolution and an increase in mean absolute error (MAE) of their Δϕs from 6.8° for 1 mm resolution to 9.5° , 12.2° , and 15.3° for 2, 4, and 8 mm resolution, respectively. These results reinforce the potential of CZT detectors to lead next generation PET systems taking full advantage of the QE information of positron annihilation photons.

Subject-aware PET Denoising with Contrastive Adversarial Domain Generalization.

Recent advances in deep learning (DL) have greatly improved the performance of positron emission tomography (PET) denoising performance. However, DL model performance can vary a lot across subjects, due to the large variability of the count levels and spatial distributions. A generalizable DL model that mitigates the subject-wise variations is highly expected toward a reliable and trustworthy system for clinical application. In this work, we propose a contrastive adversarial learning framework for subject-wise domain generalization (DG). Specifically, we configure a contrastive discriminator in addition to the UNet-based denoising module to check the subject-related information in the bottleneck feature, while the denoising module is adversarially trained to enforce the extraction of subject-invariant features. The sampled low-count realizations from the list-mode data are used as anchor-positive pairs to be close to each other, while the other subjects are used as negative samples to be distributed far away. We evaluated on 97 18F-MK6240 tau PET studies, each having 20 noise realizations with 25% fractions of events. Training, validation, and testing were implemented using 1400, 120, and 420 pairs of 3D image volumes in a subject-independent manner. The proposed contrastive adversarial DG demonstrated superior denoising performance than conventional UNet without subject-wise DG and cross-entropy-based adversarial DG.

Effect of Hyperketonemia on Myocardial Function in Patients with Heart Failure and Type 2 Diabetes.

We examined the effect of increased plasma ketones on left ventricular (LV) function, myocardial glucose uptake (MGU), and myocardial blood flow (MBF) in type 2 diabetes (T2DM) patients with heart failure (HF). Three groups (I,II,III) of T2DM (12 per group) with LV ejection fraction ≤50% received incremental infusions of β-OH-B for 3-6 hours to raise plasma β-OH-B concentration throughout the physiologic (Groups I and II) and pharmacologic (Group III) range. Cardiac MRI was performed at baseline and after each β-OH-B infusion to provide measures of cardiac function. On a separate day, Group II also received NaHCO3 infusion, thus serving as their own control for time, volume, and pH. Additionally, Group II underwent positron emission tomography study with 18F-fluoro-2-deoxyglucose to examine effect of hyperketonemia on MGU. Groups I, II, III achieved plasma β-OH-B levels of 0.7±0.3, 1.6±0.2, 3.2±0.2 mmol/L, respectively. Cardiac output, LVEF, and stroke volume increased significantly during β-OH-B infusion in Groups II (CO, 4.54 to 5.30; EF, 39.9 to 43.8; SV, 70.3 to 80.0) and III (CO, 5.93 to 7.16; EF, 41.1 to 47.5; SV, 89.0 to 108.4) and did not change with NaHCO3 infusion in Group II. The increase in LVEF was greatest in Group III (p<0.001 vs Group II). MGU and MBF were not altered by β-OH-B. In T2DM patients with LVEF≤50%, increased plasma β-OH-B significantly increased LV function dose-dependently. Since MGU did not change, the myocardial benefit of β-OH-B resulted from providing an additional fuel for the heart without inhibiting MGU.

PICASSO: a universal brain phantom for positron emission tomography based on the activity painting technique

Objective. This study presents a universal phantom for positron emission tomography (PET) that allows arbitrary static and dynamic activity distributions of various complexities to be generated using a single PET acquisition.Approach. We collected a high-statistics dataset (with a total of 22.4 × 109prompt coincidences and an event density of 2.75 × 106events mm-3) by raster-scanning a single plane with a22Na point source mounted on a robotic arm in the field-of-view of the uEXPLORER PET/CT scanner. The source position was determined from the reconstructed dynamic frames. Uniquely, true coincidences were separated from scattered and random events based on the distance between their line-of-response and the known source location. Finally, we randomly sampled the dataset to generate the desired activity distributions modeling several different phantoms.Main results. Overall, the target and the reconstructed phantom images had good agreement. The analysis of a simple geometric distribution showed high quantitative accuracy of the phantom, with mean error of <-3.0% relative to the ground truth for activity concentrations ranging from 5.3 to 47.7 kBq ml-1. The model of a high-resolution18F-fluorodeoxyglucose distribution in the brain illustrates the usefulness of the technique in simulating realistic static neuroimaging studies. A dynamic18F-florbetaben study was modeled based on the time-activity curves of a human study and a segmented brain phantom with no coincidences repeating between frames. For all time points, the mean voxel-wise errors ranged from -4.4% to -0.7% in grey matter and from -3.9% to +2.8% in white matter.Significance. The proposed phantom technique is highly flexible and allows modeling of static and dynamic brain PET studies with high quantitative accuracy. It overcomes several key limitations of the existing phantoms and has many promising applications for the purposes of image reconstruction, data correction methods, and system performance evaluation, particularly for new high-performance dedicated brain PET scanners.

Cholinergic Basal Forebrain Integrity and Cognition in Parkinson's Disease: A Reappraisal of Magnetic Resonance Imaging Evidence.

Cognitive impairment is a well-recognized and debilitating symptom of Parkinson's disease (PD). Degradation in the cortical cholinergic system is thought to be a key contributor. Both postmortem and in vivo cholinergic positron emission tomography (PET) studies have provided valuable evidence of cholinergic system changes in PD, which are pronounced in PD dementia (PDD). A growing body of literature has employed magnetic resonance imaging (MRI), a noninvasive, more cost-effective alternative to PET, to examine cholinergic system structural changes in PD. This review provides a comprehensive discussion of the methodologies and findings of studies that have focused on the relationship between cholinergic basal forebrain (cBF) integrity, based on T1- and diffusion-weighted MRI, and cognitive function in PD. Nucleus basalis of Meynert (Ch4) volume has been consistently reduced in cognitively impaired PD samples and has shown potential utility as a prognostic indicator for future cognitive decline. However, the extent of structural changes in Ch4, especially in early stages of cognitive decline in PD, remains unclear. In addition, evidence for structural change in anterior cBF regions in PD has not been well established. This review underscores the importance of continued cross-sectional and longitudinal research to elucidate the role of cholinergic dysfunction in the cognitive manifestations of PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Vitamin D’s Capacity to Increase Amphetamine-Induced Dopamine Release in Healthy Humans: A Clinical Translational [11C]-PHNO Positron Emission Tomography Study

BackgroundDopaminergic tone and phasic release have transdiagnostic relevance. Preclinical research suggests that the active form of vitamin D, calcitriol, increases subcortical tyrosine hydroxylase, D2/3 receptors, and amphetamine-stimulated dopamine release in rodents. Comparable studies have not been conducted in humans. MethodsHealthy, vitamin-D-sufficient adults (N=18; 32.8 ±6.6 years; 33% female) participated in a randomized, double-blind, placebo-controlled within-subjects study involving four total scans over two visits consisting of same-day pre-amphetamine and post-amphetamine (0.3 mg/kg) 11C-PHNO positron emission tomography (PET) scanning to examine D2/3 receptor availability (BPND) following active calcitriol (1.5 μg night before experimental day and 1.5 μg morning of experimental day) or placebo at least six days apart. Parametric images of 11C-PHNO PET BPND were computed using a simplified reference tissue model with the cerebellum as reference. Blood samples were acquired to measure serum calcitriol, amphetamine, and calcium levels. Regions of interest examined were the dorsal caudate, dorsal putamen, ventral striatum, globus pallidus, and substantia nigra. ResultsFor pre-amphetamine scans, there was a medication-by-region-of-interest interaction (F4,153=2.59, p=0.039) and a main effect of medication (F1,153=4.88, p=0.029) on BPND, with higher BPND values on calcitriol in the ventral striatum (t=2.89, p=0.004) and dorsal putamen (t=2.15, p=0.033). There was a main effect of medication on post-amphetamine change in BPND (F4,153=5.93, p=0.016), with greater decreases on calcitriol in the ventral striatum (t=3.00, p=0.003), substantia nigra (t=2.49, p=0.014), and dorsal caudate (t=2.29, p=0.023). ConclusionsResults provide translational support for vitamin D to target dopaminergic tone, with implications for clinical disorders involving dysregulated dopamine function. Clinical Trial RegistrationVitamin D as a Therapeutic Adjunct in the Stimulant Treatment of ADHD; https://clinicaltrials.gov/study/NCT03103750; ClinicalTrials.gov ID: NCT03103750

Associations between amyloid-β load and cognition in cerebrovascular disease beyond cerebral amyloid angiopathy: a systematic review and meta-analysis of positron emission tomography studies.

There is growing interest in the comorbidity of vascular and neurodegenerative pathologies in patients with cerebrovascular disease (CVD) beyond cerebral amyloid angiopathy (CAA). However, the relationship between amyloid-β and vascular cognitive impairment (VCI) remains debated. To investigate the association between VCI and amyloid-β deposition in non-CAA CVD patients. PubMed, Embase, Web of Science, PsycINFO and CENTRAL databases were systematically searched. Observational studies, including case-control and cohort studies, associating cognitive scores with amyloid load measured by positron emission tomography were selected. Meta-analyses were performed to assess the strength of amyloid-cognition associations across CVD subtypes and cognitive domains. A random-effects model using the inverse variance method was used, with heterogeneity evaluated by Q-statistics and I2 statistics. Meta-regression analyses were conducted to examine the influence of moderators, and publication bias was assessed using funnel plots and Egger's test. All statistical analyses were performed using StataMP 18. Twenty-seven eligible studies encompassing 2894 participants were included. Among non-CAA CVD patients, global cognitive performance was significantly lower in those with higher amyloid-β deposition (standardized mean difference = -0.43, P < 0.001). The correlation strength varied across cognitive domains (executive function: r = -0.41; language: r = -0.36; memory: r = -0.29; all P < 0.001). The correlation was significant in patients with subcortical vascular disease (r = -0.43, P < 0.001) but not post-stroke patients (r = -0.19, P > 0.05). Amyloid-β load is associated with cognitive decline in non-CAA CVD patients. This is more pronounced in patients with subcortical vascular disease than in post-stroke patients. Executive function is the most susceptible domain in VCI when the level of amyloid-β increases.

Radiological Diagnosis and Advances in Imaging of Vertebral Compression Fractures.

Vertebral compression fractures (VCFs) affect 1.4 million patients every year, especially among the globally aging population, leading to increased morbidity and mortality. Often characterized with symptoms of sudden onset back pain, decreased vertebral height, progressive kyphosis, and limited mobility, VCFs can significantly impact a patient's quality of life and are a significant public health concern. Imaging modalities in radiology, including radiographs, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) studies and bone scans, play crucial and evolving roles in the diagnosis, assessment, and management of VCFs. An understanding of anatomy, and the extent to which each imaging modality serves to elucidate that anatomy, is crucial in understanding and providing guidance on fracture severity, classification, associated soft tissue injuries, underlying pathologies, and bone mineral density, ultimately guiding treatment decisions, monitoring treatment response, and predicting prognosis and long-term outcomes. This article thus explores the important role of radiology in illuminating the underlying anatomy and pathophysiology, classification, diagnosis, treatment, and management of patients with VCFs. Continued research and advancements in imaging technologies will further enhance our understanding of VCFs and pave the way for personalized and effective management strategies.

Preclinical Evaluation of Dihydropyrazole-Cored Positron Emission Tomography (PET) Ligands for Imaging of Receptor-Interacting Serine/Threonine Protein Kinase 1 (RIPK1) in the Brain.

Receptor-interacting serine/threonine protein kinase 1 (RIPK1) has emerged as an important regulator of pathologic cell death and inflammation and is implicated in the pathologies of various central nervous system diseases. In this study, we reported the development of three potent dihydropyrazole-cored RIPK1 positron emission tomography (PET) ligands [18F]WL1-3. Among these, [18F]WL1 showed specific binding to RIPK1 in mouse brain sections in vitro through autoradiography and exhibited favorable brain kinetics in mice, characterized by a high initial uptake (brain2 min = 4.89% ID/g) and rapid washout (brain60 min = 0.21% ID/g). PET studies in rat brains revealed that [18F]WL1 could readily penetrate the brain with specific binding confirmed by inhibition effects of unlabeled WL1 and GSK'547. Notably, [18F]WL1 showed significant potential in imaging the alterations of RIPK1 in a rat brain of tumor necrosis factor α-induced systemic inflammatory response syndrome model. These findings may pave the way for the future design of potent RIPK1 PET ligands.

Assessment of the relationship between synaptic density and metabotropic glutamate receptors in early Alzheimer's disease: a multi-tracer PET study.

The pathological effects of amyloid β oligomers (Aβo) may be mediated through the metabotropic glutamate receptor subtype 5 (mGluR5), leading to synaptic loss in Alzheimer's disease (AD). Positron emission tomography (PET) studies of mGluR5 using [18F]FPEB indicate a reduction of receptor binding that is focused in the medial temporal lobe in AD. Synaptic loss due to AD measured through synaptic vesicle glycoprotein 2A (SV2A) quantification with [11C]UCB-J PET is also focused in the medial temporal lobe, but with clear widespread reductions is commonly AD-affected neocortical regions. In this study, we used [18F]FPEB and [11C]UCB-J PET to investigate the relationship between mGluR5 and synaptic density in early AD. Fifteen amyloid positive participants with early AD and 12 amyloid negative, cognitively normal (CN) participants underwent PET scans with both [18F]FPEB to measure mGluR5 and [11C]UCB-J to measure synaptic density. Parametric DVR images using equilibrium methods were generated from dynamic. For [18F]FPEB PET, DVR was calculated using equilibrium methods and a cerebellum reference region. For [11C]UCB-J PET, DVR was calculated with a simplified reference tissue model - 2 and a whole cerebellum reference region.. A strong positive correlation between mGluR5 and synaptic density was present in the hippocampus for participants with AD (r = 0.81, p < 0.001) and in the CN group (r = 0.74, p = 0.005). In the entorhinal cortex, there was a strong positive correlation between mGluR5 and synaptic in the AD group (r = 0.85, p <0.001), but a weaker non-significant correlation in the CN group (r = 0.36, p = 0.245). Exploratory analyses within and between other brain regions suggested significant positive correlations between mGluR5 in the medial temporal lobe and synaptic density in a broader set of commonly AD-affected regions. Medial temporal loss of mGluR5 in AD is associated with synaptic loss in both medial temporal regions and more broadly in association cortical regions, indicating that mGluR5 mediated Aβo toxicity may lead to early synaptic loss more broadly in AD-affected networks. In CN individuals, an isolated strong association between lower mGluR5 and lower synaptic density may indicate non-AD related synaptic loss.

Topography of Cholinergic Nerve Terminal Vulnerability and Balance Self-Efficacy in Parkinson's Disease.

Postural instability and gait disturbances (PIGD) represent a significant cause of disability in Parkinson's disease (PD). Cholinergic system dysfunction has been implicated in falls in PD. The occurrence of falls typically results in fear of falling (FoF) that in turn may lead to poorer balance self-efficacy. Balance self-efficacy refers to one's level of confidence in their ability to balance while completing activities of daily living like getting dressed, bathing, and walking. Lower self-efficacy, or greater FoF during these activities is a function of motor, cognitive, and emotional impairments and may impact quality of life in PD. Unlike known cholinergic reduction, especially in the right lateral geniculate and caudate nuclei, little is known about the role of cholinergic transporters in FoF or mobility self-efficacy in PD. [18F]fluoroethoxybenzovesamicol ([18F]FEOBV) positron emission tomography (PET) studies were conducted to assess vesicular acetylcholine transporter (VAChT) expression in 126 patients with PD (male (m) = 95, female (f) = 31). Participants had a mean age of 67.3 years (standard deviation (SD) = 7.1) and median Hoehn Yahr stage of 2.5. Patients also completed the Short Falls Efficacy Scale (sFES-I) as a survey measure of concerns about falling. [18F]FEOBV data were processed in Statistical Parametric Mapping (SPM) using a voxel-wise regression model with sFES-I scores as the outcome measure. Reduced [18F]FEOBV binding in tectum, metathalamic (lateral more than medial geniculate nuclei), thalamus proper, bilateral mesiotemporal (hippocampal, parahippocampal, fusiform gyri and fimbriae), and right cerebellar lobule VI significantly associated with higher sFES-I scores (p < 0.05, family-wise error (FWE) correction after Threshold-Free Cluster Enhancement (TFCE)). Unlike the more limited involvement of the brainstem-thalamic complex and caudate nuclei cholinergic topography associated with falls in PD, cholinergic reductions in the extended connectivity between the thalamic complex and the temporal limbic system via the fimbriae associates with FoF. Additional cholinergic changes were seen in the cerebellum. The temporal limbic system plays a role not only in episodic memory but also in spatial navigation, scene and contextual (e.g., emotional) processing. Findings may augur novel therapeutic approaches to treat poor mobility self-efficacy in PD. No: NCT02458430. Registered 18 March, 2015, https://www. gov/study/NCT02458430; No: NCT05459753. Registered 01 July, 2022, https://www. gov/study/NCT05459753.

Synthesis and Evaluation of 18F-Labeled Phenylpiperazine-like Dopamine D3 Receptor Radioligands for Positron Emission Tomography Imaging.

The dopamine D3 receptor (D3R) is important in the pathophysiology of various neuropsychiatric disorders, such as depression, bipolar disorder, schizophrenia, drug addiction, and Parkinson's disease. Positron emission tomography (PET) with innovative radioligands provides an opportunity to assess D3R in vivo and to elucidate D3R-related disease mechanisms. Herein, we present the synthesis of eight 18F-labeled phenylpiperazine-like D3R-selective radioligands possessing good radiochemical purity (>97%), in vitro stability (>95%), and befitting lipophilicity. Based on in vitro binding assays and static microPET studies, the phenylpiperazine-like radioligands [18F]FBPC01 and [18F]FBPC03 were chosen as lead radioligands targeting D3R. Molecular docking further elucidated their binding mechanism. Radiolabeling conditions were optimized and then applied to an automated radiolabeling process, affording products with high specific activity (>112 GBq/μmol). Dynamic rat PET study demonstrated the specific binding of [18F]FBPC01 and [18F]FBPC03 to D3R in the brain ventricles and the pituitary gland. Validated by dynamic PET data analysis, biodistribution study, and metabolism analysis, [18F]FBPC03 exhibited the highest PET signal-to-noise ratio, good D3R-specific binding in the brain ventricles and pituitary gland of rats with few off-target binding, negligible defluorination, and stable brain metabolism, which indicated that [18F]FBPC03 was a promising D3R radioligand.

Automated, Transferable, and Ethanol-Free Radiosynthesis of [11C]Butanol.

Cerebral blood flow and blood-brain barrier permeability assessment are crucial hemodynamic parameters to measure under neurological conditions. In conjunction with positron emission tomography (PET), oxygen-15-labeled water has emerged as a gold standard for measuring cerebral perfusion; however, at higher flow rates, [15O]water extraction becomes nonlinear. In such a scenario, freely diffusible [11C]butanol can provide a truer estimate. Radiosyntheses of [11C]butanol reported to date are protracted, are not automated, or require ethanol in the final formulation. By using a flow-based, captive solvent approach on a commercially available radiosynthesizer, we automated and reduced the synthesis time to 28 min. Forgoing cartridge-based purification for an aqueous high-performance liquid chromatography method, we obtained high purity [11C]butanol in ethanol-free phosphate buffered saline in sufficient yields for clinical PET studies. We here report our expedited, automated, and ethanol-free radiosynthesis of [11C]butanol along with preliminary imaging of a porcine subject.

Structure-based discovery of a 4,5-Dihydropyrazole-cored PET ligand for imaging of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) in the brain

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) regulates programmed cell death and inflammation, contributing to a wide range of human pathologies, including inflammatory disorders, neurodegenerative conditions, and cancer. Despite this, no RIPK1 positron emission tomography (PET) ligand with significant in vivo specificity has been reported to date. In this work, we designed and synthesized a new family of dihydropyrazole-cored ligands suitable for 18F-labeling at the late stage. Among these, WL8 showed a strong binding affinity to RIPK1 (EC50 = 19.9 nM, Kd = 25 nM) and was successfully labeled with 18F in the 6-position of pyridine ring, yielding a high radiochemistry yield of 27.9 % (decay-corrected) and a high molar activity of 18.8–31.2 GBq/μmol. In in vitro autoradiography, [18F]WL8 showed some specific binding in the brain sections of rats and lipopolysaccharide (LPS) model mice. Preliminary PET studies in rat brains revealed that [18F]WL8 could efficiently penetrate the blood-brain barrier and was rapidly washed out. As anticipated, [18F]WL8 exhibited a high initial uptake (brain2min = 4.80 % ID/g) in mouse brains, followed by a rapid washout (brain60min = 0.14 % ID/g), although no clear specific binding to RIPK1 was observed. Moderate in vivo stability was noted for [18F]WL8 in mouse brains with 35.2 % of the parent fraction remaining after 30 min post-administration. Altogether, our work broadens the landscape and offers a new chemotype for RIPK1 PET ligand development.

Tau Deposition in Secondary Thalamic Degeneration due to Cerebral Infarction in Humans: A Florzolotau (18F) Positron Emission Tomography Study.

Tau Deposition in Secondary Thalamic Degeneration due to Cerebral Infarction in Humans: A Florzolotau (18F) Positron Emission Tomography Study.