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While all reversible receptor-targeting radioligands for positron emission tomography (PET) can be displaced by competition with an antagonist at the receptor, many radiotracers show limited occupancies using agonists even at high doses. [11C]Raclopride, a D2/D3 receptor radiotracer with rapid kinetics, can identify the direction of changes in the neurotransmitter dopamine, but quantitative interpretation of the relationship between dopamine levels and radiotracer binding has proven elusive. Agonist-induced receptor desensitization and internalization, a homeostatic mechanism to downregulate neurotransmitter-mediated function, can shift radioligand-receptor binding affinity and confound PET interpretations of receptor occupancy. In this study, we compared occupancies induced by amphetamine (AMP) in drug-naive wild-type (WT) and internalization-compromised β-arrestin-2 knockout (KO) mice using a within-scan drug infusion to modulate the kinetics of [11C]raclopride. We additionally performed studies at 3 h following AMP pretreatment, with the hypothesis that receptor internalization should markedly attenuate occupancy on the second challenge, because dopamine cannot access internalized receptors. Without prior AMP treatment, WT mice exhibited somewhat larger binding potential than KO mice but similar AMP-induced occupancy. At 3 h after AMP treatment, WT mice exhibited binding potentials that were 15 % lower than KO mice. At this time point, occupancy was preserved in KO mice but suppressed by 60 % in WT animals, consistent with a model in which most receptors contributing to binding potential in WT animals were not functional. These results demonstrate that arrestin-mediated receptor desensitization and internalization produce large effects in PET [11C]raclopride occupancy studies using agonist challenges.

In 2019, the National Health Interview survey found that nearly 59% of adults reported pain some, most, or every day in the past 3 months, with 39% reporting back pain, making back pain the most prevalent source of pain, and a significant issue among adults. Often, identifying a direct, treatable cause for back pain is challenging, especially as it is often attributed to complex, multifaceted issues involving biological, psychological, and social components. Due to the difficulty in treating the true cause of chronic low back pain (cLBP), an over-reliance on opioid pain medications among cLBP patients has developed, which is associated with increased prevalence of opioid use disorder and increased risk of death. To combat the rise of opioid-related deaths, the National Institutes of Health (NIH) initiated the Helping to End Addiction Long-TermSM (HEAL) initiative, whose goal is to address the causes and treatment of opioid use disorder while also seeking to better understand, diagnose, and treat chronic pain. The NIH Back Pain Consortium (BACPAC) Research Program, a network of 14 funded entities, was launched as a part of the HEAL initiative to help address limitations surrounding the diagnosis and treatment of cLBP. This paper provides an overview of the BACPAC research program's goals and overall structure, and describes the harmonization efforts across the consortium, define its research agenda, and develop a collaborative project which utilizes the strengths of the network. The purpose of this paper is to serve as a blueprint for other consortia tasked with the advancement of pain related science.

Targeting receptor‐interacting protein kinase 1 (RIPK1) has emerged as a promising therapeutic stratagem for neurodegenerative disorders, particularly Alzheimer's disease (AD). A positron emission tomography (PET) probe enabling brain RIPK1 imaging can provide a powerful tool to unveil the neuropathology associated with RIPK1. Herein, the development of a new PET radioligand, [11C]CNY‐10 is reported, which may enable brain RIPK1 imaging. [11C]CNY‐10 is radiosynthesized with a high radiochemical yield (41.8%) and molar activity (305 GBq/µmol). [11C]CNY‐10 is characterized by PET imaging in rodents and a non‐human primate, demonstrating good brain penetration, binding specificity, and a suitable clearance kinetic profile. It is performed autoradiography of [11C]CNY‐10 in human AD and healthy control postmortem brain tissues, which shows strong radiosignal in AD brains higher than healthy controls. Subsequently, it is conducted further characterization of RIPK1 in AD using [11C]CNY‐10‐based PET studies in combination with immunohistochemistry leveraging the 5xFAD mouse model. It is found that AD mice revealed RIPK1 brain signal significantly higher than WT control mice and that RIPK1 is closely related to amyloid plaques in the brain. The studies enable further translational studies of [11C]CNY‐10 for AD and potentially other RIPK1‐related human studies. [ABSTRACT FROM AUTHOR]

MRI and PET provide complementary information for studying brain function. While the potential use of simultaneous MRI/PET for clinical diagnostic and disease staging has been demonstrated recently; the biological relevance of concurrent functional MRI-PET brain imaging to dissect neurochemically distinct components of the blood oxygenation level dependent (BOLD) fMRI signal has not yet been shown. We obtained sixteen fMRI-PET data sets from eight healthy volunteers. Each subject participated in randomized order in a pain scan and a control (nonpainful pressure) scan on the same day. Dynamic PET data were acquired with an opioid radioligand, [(11)C]diprenorphine, to detect endogenous opioid releases in response to pain. BOLD fMRI data were collected at the same time to capture hemodynamic responses. In this simultaneous human fMRI-PET imaging study, we show co-localized responses in thalamus and striatum related to pain processing, while modality specific brain networks were also found. Co-localized fMRI and PET signal changes in the thalamus were positively correlated suggesting that pain-induced changes in opioid neurotransmission contribute a significant component of the fMRI signal change in this region. Simultaneous fMRI-PET provides unique opportunities allowing us to relate specific neurochemical events to functional hemodynamic activation and to investigate the impacts of neurotransmission on neurovascular coupling of the human brain in vivo.

BACKGROUND. Patients with schizophrenia (SCZ) experience chronic cognitive deficits. Histone deacetylases (HDACs) are enzymes that regulate cognitive circuitry; however, the role of HDACs in cognitive disorders, including SCZ, remains unknown in humans. We previously determined that HDAC2 mRNA levels were lower in dorsolateral prefrontal cortex (DLPFC) tissue from donors with SCZ compared with controls. Here we investigated the relationship between in vivo HDAC expression and cognitive impairment in patients with SCZ and matched healthy controls using [11C]Martinostat positron emission tomography (PET).METHODS. In a case-control study, relative [11C]Martinostat uptake was compared between 14 patients with SCZ or schizoaffective disorder (SCZ/SAD) and 17 controls using hypothesis-driven region-of-interest analysis and unbiased whole brain voxel-wise approaches. Clinical measures, including the MATRICS consensus cognitive battery, were administered.RESULTS. Relative HDAC expression was lower in the DLPFC of patients with SCZ/SAD compared with controls, and HDAC expression positively correlated with cognitive performance scores across groups. Patients with SCZ/SAD also showed lower relative HDAC expression in the dorsomedial prefrontal cortex and orbitofrontal gyrus, and higher relative HDAC expression in the cerebral white matter, pons, and cerebellum compared with controls.CONCLUSIONS. These findings provide in vivo evidence of HDAC dysregulation in patients with SCZ and suggest that altered HDAC expression may impact cognitive function in humans.FUNDING. National Institute of Mental Health (NIMH), Brain and Behavior Foundation, Massachusetts General Hospital (MGH), Athinoula A. Martinos Center for Biomedical Imaging, National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH Shared Instrumentation Grant Program., IntroductionEpigenetic mechanisms have been associated with cognitive function through postmortem human and preclinical studies (1-3), but no direct associations have been made in the living human brain. This is because [...]

Olfactory dysfunction is broadly associated with neurodevelopmental and neurodegenerative diseases and predicts increased mortality rates in healthy individuals. Conventional measurements of olfactory health assess odor processing pathways within the brain and provide a limited understanding of primary odor detection. Quantification of the olfactory sensory neurons (OSNs), which detect odors within the nasal cavity, would provide insight into the etiology of olfactory dysfunction associated with disease and mortality. Notably, OSNs are continually replenished by adult neurogenesis in mammals, including humans, so OSN measurements are primed to provide specialized insights into neurological disease. Here, we have evaluated a PET radiotracer, [[sup.11]C]GV1-57, that specifically binds mature OSNs and quantifies the mature OSN population in vivo. [[sup.11]C]GV1-57 monitored native OSN population dynamics in rodents, detecting OSN generation during postnatal development and aging-associated neurodegeneration. [[sup.11]C]GV1-57 additionally measured rates of neuron regeneration after acute injury and early-stage OSN deficits in a rodent tauopathy model of neurodegenerative disease. Preliminary assessment in nonhuman primates suggested maintained uptake and saturable binding of [[sup.18]F]GV1-57 in primate nasal epithelium, supporting its translational potential. Future applications for GV1-57 include monitoring additional diseases or conditions associated with olfactory dysregulation, including cognitive decline, as well as monitoring effects of neuroregenerative or neuroprotective therapeutics., Introduction Olfactory function may serve as a general marker of brain health. In neurodevelopmental disease, patients with intellectual disability, e.g., Down syndrome and idiopathic intellectual disability, or later-onset neurodevelopmental disorders, [...]

Alzheimer's disease (AD) is characterized by the brain accumulation of amyloid-β and tau proteins. A growing body of literature suggests that epigenetic dysregulations play a role in the interplay of hallmark proteinopathies with neurodegeneration and cognitive impairment. Here, we aim to characterize an epigenetic dysregulation associated with the brain deposition of amyloid-β and tau proteins. Using positron emission tomography (PET) tracers selective for amyloid-β, tau, and class I histone deacetylase (HDAC I isoforms 1–3), we find that HDAC I levels are reduced in patients with AD. HDAC I PET reduction is associated with elevated amyloid-β PET and tau PET concentrations. Notably, HDAC I reduction mediates the deleterious effects of amyloid-β and tau on brain atrophy and cognitive impairment. HDAC I PET reduction is associated with 2-year longitudinal neurodegeneration and cognitive decline. We also find HDAC I reduction in the postmortem brain tissue of patients with AD and in a transgenic rat model expressing human amyloid-β plus tau pathology in the same brain regions identified in vivo using PET. These observations highlight HDAC I reduction as an element associated with AD pathophysiology. The link between amyloid and tau proteins with Alzheimer's disease progression remains unclear. Here, the authors propose HDACs I downregulation as an element linking the deleterious effects of brain proteinopathies with disease progression. [ABSTRACT FROM AUTHOR]

Background: Although aberrant intrinsic functional connectivity has been reported in attention-deficit/hyperactivity disorder (ADHD), we have a limited understanding of whether connectivity alterations are related to the familial risk of ADHD. Methods: Fifty-three probands with ADHD, their unaffected siblings (n = 53) and typically developing controls (n = 53) underwent resting-state functional magnetic resonance imaging scans. A seed-based approach with the bilateral precuneus/posterior cingulate cortex (PCC) was used to derive a whole-brain functional connectivity map in each subject. The differences in functional connectivity among the three groups were tested with one-way ANOVA using randomized permutation. Comparisons between two groups were also performed to examine the increase or decrease in connectivity. The severity of ADHD symptoms was used to identify brain regions where symptom severity is correlated to the strength of intrinsic functional connectivity. Results: When compared to controls, both probands and unaffected siblings showed increased functional connectivity in the left insula and left inferior frontal gyrus. The connectivity in these regions was linked to better performance in response inhibition in the control group but absent in other groups. Higher ADHD symptom severity was correlated with increased functional connectivity in bilateral fronto-parietal-temporal regions only noted in probands with ADHD. Conclusions: Alterations in resting-state functional connectivities with the precuneus/PCC, hubs of default-mode network, account for the underlying familial risks of ADHD. Since the left insula and left inferior frontal gyri are key regions of the salience and frontoparietal network, respectively, future studies focusing on alterations of cross-network functional connectivity as the familial risk of ADHD are suggested. [ABSTRACT FROM AUTHOR]