scholarly journals ADORA2A variation and adenosine A1 receptor availability in the human brain with a focus on anxiety-related brain regions: modulation by ADORA1 variation

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Christa Hohoff ◽  
Tina Kroll ◽  
Baoyuan Zhao ◽  
Nicole Kerkenberg ◽  
Ilona Lang ◽  
...  
Keyword(s):  
Brain Regions ◽  
Phenotypic Characterization ◽  
Gene Variation ◽  
Quantitative Pet ◽  
Positron Emission ◽  
A1 Receptor ◽  
Magnetic Resonance Imaging Mri ◽  
Post Hoc ◽  
The Relationship

AbstractAdenosine, its interacting A1 and A2A receptors, and particularly the variant rs5751876 in the A2A gene ADORA2A have been shown to modulate anxiety, arousal, and sleep. In a pilot positron emission tomography (PET) study in healthy male subjects, we suggested an effect of rs5751876 on in vivo brain A1 receptor (A1AR) availability. As female sex and adenosinergic/dopaminergic interaction partners might have an impact on this rs5751876 effect on A1AR availability, we aimed to (1) further investigate the pilot male-based findings in an independent, newly recruited cohort including women and (2) analyze potential modulation of this rs5751876 effect by additional adenosinergic/dopaminergic gene variation. Healthy volunteers (32/11 males/females) underwent phenotypic characterization including self-reported sleep and A1AR-specific quantitative PET. Rs5751876 and 31 gene variants of adenosine A1, A2A, A2B, and A3 receptors, adenosine deaminase, and dopamine D2 receptor were genotyped. Multivariate analysis revealed an rs5751876 effect on A1AR availability (P = 0.047), post hoc confirmed in 30 of 31 brain regions (false discovery rate (FDR) corrected P values < 0.05), but statistically stronger in anxiety-related regions (e.g., amygdala, hippocampus). Additional effects of ADORA1 rs1874142 were identified; under its influence rs5751876 and rs5751876 × sleep had strengthened effects on A1AR availability (Pboth < 0.02; post hoc FDR-corrected Ps < 0.05 for 29/30 regions, respectively). Our results support the relationship between rs5751876 and A1AR availability. Additional impact of rs1874142, together with rs5751876 and sleep, might be involved in regulating arousal and thus the development of mental disorders like anxiety disorders. The interplay of further detected suggestive ADORA2A × DRD2 interaction, however, necessitates larger future samples more comparable to magnetic resonance imaging (MRI)-based samples.

scholarly journals Seasonal variation in brain mu-opioid receptor availability

2020 ◽  
Author(s):  
Lihua Sun ◽  
Jing Tang ◽  
Heidi Liljenbäck ◽  
Aake Honkaniemi ◽  
Jenni Virta ◽  
...  
Keyword(s):  
Seasonal Variation ◽  
Opioid Receptor ◽  
Causal Effect ◽  
Brain Regions ◽  
Seasonal Effects ◽  
Positron Emission ◽  
Significant Seasonal Variation ◽  
Normal Humans ◽  
Post Hoc

AbstractSeasonal rhythms influence mood and sociability. The brain μ-opioid receptor (MOR) system modulates a multitude of seasonally varying socioemotional functions, but its seasonal variation remains elusive with no previously reported in vivo evidence. Here, we studied the seasonal effects on brain MOR availability via analysing a dataset (n=204) of [11C]carfentanil positron emission tomography (PET) scans of healthy volunteers. We found that seasonally varying daylength had an inverted U-shaped functional relationship with brain MOR availability. Brain regions sensitive to daylength spanned the socio-emotional brain circuits, where MOR availability formed a spring-like peak. Causal effect of daylength on brain MOR availability was further verified by a post hoc experiment with repeated PET imaging of rats (n=9) under seasonal photoperiodic simulation. Therefore, the in vivo brain MOR availability in normal humans shows significant seasonal variation, which aligns with expected seasonal variation in mood and suicidality.

scholarly journals The pharmacokinetics of [18F]UCB-H revisited in the healthy non-human primate brain

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sébastien Goutal ◽  
Martine Guillermier ◽  
Guillaume Becker ◽  
Mylène Gaudin ◽  
Yann Bramoullé ◽  
...  
Keyword(s):  
Slow Component ◽  
Specific Binding ◽  
Compartment Model ◽  
Brain Regions ◽  
Volume Of Distribution ◽  
Pharmacokinetic Data ◽  
Limited Information ◽  
Positron Emission ◽  
Human Primate

Abstract Background Positron Emission Tomography (PET) imaging of the Synaptic Vesicle glycoprotein (SV) 2A is a new tool to quantify synaptic density. [18F]UCB-H was one of the first promising SV2A-ligands to be labelled and used in vivo in rodent and human, while limited information on its pharmacokinetic properties is available in the non-human primate. Here, we evaluate the reliability of the three most commonly used modelling approaches for [18F]UCB-H in the non-human cynomolgus primate, adding the coupled fit of the non-displaceable distribution volume (VND) as an alternative approach to improve unstable fit. The results are discussed in the light of the current state of SV2A PET ligands. Results [18F]UCB-H pharmacokinetic data was optimally fitted with a two-compartment model (2TCM), although the model did not always converge (large total volume of distribution (VT) or large uncertainty of the estimate). 2TCM with coupled fit K1/k2 across brain regions stabilized the quantification, and confirmed a lower specific signal of [18F]UCB-H compared to the newest SV2A-ligands. However, the measures of VND and the influx parameter (K1) are similar to what has been reported for other SV2A ligands. These data were reinforced by displacement studies using [19F]UCB-H, demonstrating only 50% displacement of the total [18F]UCB-H signal at maximal occupancy of SV2A. As previously demonstrated in clinical studies, the graphical method of Logan provided a more robust estimate of VT with only a small bias compared to 2TCM. Conclusions Modeling issues with a 2TCM due to a slow component have previously been reported for other SV2A ligands with low specific binding, or after blocking of specific binding. As all SV2A ligands share chemical structural similarities, we hypothesize that this slow binding component is common for all SV2A ligands, but only hampers quantification when specific binding is low.

scholarly journals Cellular sources of TSPO expression in healthy and diseased brain

2021 ◽  
Author(s):  
Erik Nutma ◽  
Kelly Ceyzériat ◽  
Sandra Amor ◽  
Stergios Tsartsalis ◽  
Philippe Millet ◽  
...  
Keyword(s):  
Cell Activity ◽  
Brain Regions ◽  
Cellular Level ◽  
Translocator Protein ◽  
Disease Stage ◽  
Animal Models Of Disease ◽  
Positron Emission ◽  
Neuropsychiatric Diseases ◽  
Tspo Expression

AbstractThe 18 kDa translocator protein (TSPO) is a highly conserved protein located in the outer mitochondrial membrane. TSPO binding, as measured with positron emission tomography (PET), is considered an in vivo marker of neuroinflammation. Indeed, TSPO expression is altered in neurodegenerative, neuroinflammatory, and neuropsychiatric diseases. In PET studies, the TSPO signal is often viewed as a marker of microglial cell activity. However, there is little evidence in support of a microglia-specific TSPO expression. This review describes the cellular sources and functions of TSPO in animal models of disease and human studies, in health, and in central nervous system diseases. A discussion of methods of analysis and of quantification of TSPO is also presented. Overall, it appears that the alterations of TSPO binding, their cellular underpinnings, and the functional significance of such alterations depend on many factors, notably the pathology or the animal model under study, the disease stage, and the involved brain regions. Thus, further studies are needed to fully determine how changes in TSPO binding occur at the cellular level with the ultimate goal of revealing potential therapeutic pathways.

scholarly journals PET Scan Perfusion Imaging in the Prader–Willi Syndrome: New Insights into the Psychiatric and Social Disturbances

2010 ◽  
Vol 31 (1) ◽  
pp. 275-282 ◽  
Author(s):  
Carine Mantoulan ◽  
Pierre Payoux ◽  
Gwenaëlle Diene ◽  
Mélanie Glattard ◽  
Bernadette Rogé ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Severe Disabilities ◽  
Brain Regions ◽  
Pet Scan ◽  
Prader Willi Syndrome ◽  
Behavioral Skills ◽  
Positron Emission ◽  
Functional Consequences ◽  
Magnetic Resonance Imaging Mri ◽  
Pet Scans

The Prader–Willi syndrome (PWS), a rare multisystem genetic disease, leads to severe disabilities, such as morbid obesity, endocrine dysfunctions, psychiatric disorders, and social disturbances. We explored the whole brain of patients with PWS to detect abnormalities that might explain the behavioral and social disturbances, as well as the psychiatric disorders of these patients. Nine patients with PWS (six males, three females; mean age 16.4 years) underwent a positron emission tomography (PET) scan with H215O as a tracer to measure regional cerebral blood flow (rCBF). The images were compared with those acquired from nine controls (six males, three females; mean age 21.2 years). A morphologic magnetic resonance imaging (MRI) was also performed in PWS patients, and their cognitive and behavioral skills were assessed with Wechsler Intelligence Scale for Children III and the Child Behavior Check List (CBCL). The MRI images showed no evident anatomic abnormalities, whereas PET scans revealed hypoperfused brain regions in PWS patients compared with controls, particularly in the anterior cingulum and superior temporal regions. We observed a significant relationship ( P<0.05) between rCBF in the hypoperfused regions and CBCL scores. The functional consequences of these perfusion abnormalities in specific brain regions might explain the behavioral and social problems observed in these individuals.

scholarly journals Determination of receptor occupancy in the presence of mass dose: [11C]GSK189254 PET imaging of histamine H3 receptor occupancy by PF-03654746

2016 ◽  
Vol 37 (3) ◽  
pp. 1095-1107 ◽  
Author(s):  
Jean-Dominique Gallezot ◽  
Beata Planeta ◽  
Nabeel Nabulsi ◽  
Donna Palumbo ◽  
Xiaoxi Li ◽  
...  
Keyword(s):  
Binding Sites ◽  
Human Subjects ◽  
Receptor Occupancy ◽  
Healthy Human ◽  
Positron Emission ◽  
Relationship Of ◽  
The Relationship ◽  
Pet Scans

Measurements of drug occupancies using positron emission tomography (PET) can be biased if the radioligand concentration exceeds “tracer” levels. Negative bias would also arise in successive PET scans if clearance of the radioligand is slow, resulting in a carryover effect. We developed a method to (1) estimate the in vivo dissociation constant Kd of a radioligand from PET studies displaying a non-tracer carryover (NTCO) effect and (2) correct the NTCO bias in occupancy studies taking into account the plasma concentration of the radioligand and its in vivo Kd. This method was applied in a study of healthy human subjects with the histamine H3 receptor radioligand [11C]GSK189254 to measure the PK-occupancy relationship of the H3 antagonist PF-03654746. From three test/retest studies, [11C]GSK189254 Kd was estimated to be 9.5 ± 5.9 pM. Oral administration of 0.1 to 4 mg of PF-03654746 resulted in occupancy estimates of 71%–97% and 30%–93% at 3 and 24 h post-drug, respectively. NTCO correction adjusted the occupancy estimates by 0%–15%. Analysis of the relationship between corrected occupancies and PF-03654746 plasma levels indicated that PF-03654746 can fully occupy H3 binding sites ( ROmax = 100%), and its IC50 was estimated to be 0.144 ± 0.010 ng/mL. The uncorrected IC50 was 26% higher.

Changes in synaptic density in the subacute phase after ischemic stroke: A 11C-UCB-J PET/MR study

2021 ◽  
pp. 0271678X2110477
Author(s):  
Laura Michiels ◽  
Nathalie Mertens ◽  
Liselot Thijs ◽  
Ahmed Radwan ◽  
Stefan Sunaert ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Standardized Uptake Value ◽  
Brain Regions ◽  
Asymmetry Index ◽  
Cerebellar Hemisphere ◽  
Future Research ◽  
Stroke Patients ◽  
Synaptic Density ◽  
Positron Emission

Functional alterations after ischemic stroke have been described with Magnetic Resonance Imaging (MRI) and perfusion Positron Emission Tomography (PET), but no data on in vivo synaptic changes exist. Recently, imaging of synaptic density became available by targeting synaptic vesicle protein 2 A, a protein ubiquitously expressed in all presynaptic nerve terminals. We hypothesized that in subacute ischemic stroke loss of synaptic density can be evaluated with 11C-UCB-J PET in the ischemic tissue and that alterations in synaptic density can be present in brain regions beyond the ischemic core. We recruited ischemic stroke patients to undergo 11C-UCB-J PET/MR imaging 21 ± 8 days after stroke onset to investigate regional 11C-UCB-J SUVR (standardized uptake value ratio). There was a decrease (but residual signal) of 11C-UCB-J SUVR within the lesion of 16 stroke patients compared to 40 healthy controls (ratiolesion/controls = 0.67 ± 0.28, p = 0.00023). Moreover, 11C-UCB-J SUVR was lower in the non-lesioned tissue of the affected hemisphere compared to the unaffected hemisphere (ΔSUVR = −0.17, p = 0.0035). The contralesional cerebellar hemisphere showed a lower 11C-UCB-J SUVR compared to the ipsilesional cerebellar hemisphere (ΔSUVR = −0.14, p = 0.0048). In 8 out of 16 patients, the asymmetry index suggested crossed cerebellar diaschisis. Future research is required to longitudinally study these changes in synaptic density and their association with outcome.

scholarly journals Automatic Segmentation of the Dorsal Claustrum in Humans Using in vivo High-Resolution MRI

2020 ◽  
Vol 1 (1) ◽  
Author(s):  
Shai Berman ◽  
Roey Schurr ◽  
Gal Atlan ◽  
Ami Citri ◽  
Aviv A Mezer
Keyword(s):  
High Resolution ◽  
Automatic Segmentation ◽  
Thin Sheet ◽  
Brain Regions ◽  
Reproducible Research ◽  
Human Connectome Project ◽  
High Resolution Mri ◽  
Magnetic Resonance Imaging Mri ◽  
And Function

Abstract The claustrum is a thin sheet of neurons enclosed by white matter and situated between the insula and the putamen. It is highly interconnected with sensory, frontal, and subcortical regions. The deep location of the claustrum, with its fine structure, has limited the degree to which it could be studied in vivo. Particularly in humans, identifying the claustrum using magnetic resonance imaging (MRI) is extremely challenging, even manually. Therefore, automatic segmentation of the claustrum is an invaluable step toward enabling extensive and reproducible research of the anatomy and function of the human claustrum. In this study, we developed an automatic algorithm for segmenting the human dorsal claustrum in vivo using high-resolution MRI. Using this algorithm, we segmented the dorsal claustrum bilaterally in 1068 subjects of the Human Connectome Project Young Adult dataset, a publicly available high-resolution MRI dataset. We found good agreement between the automatic and manual segmentations performed by 2 observers in 10 subjects. We demonstrate the use of the segmentation in analyzing the covariation of the dorsal claustrum with other brain regions, in terms of macro- and microstructure. We identified several covariance networks associated with the dorsal claustrum. We provide an online repository of 1068 bilateral dorsal claustrum segmentations.

scholarly journals Cerebral Microinfarcts: A Systematic Review of Neuropathological Studies

2012 ◽  
Vol 32 (3) ◽  
pp. 425-436 ◽  
Author(s):  
Manon Brundel ◽  
Jeroen de Bresser ◽  
Jeroen J van Dillen ◽  
L Jaap Kappelle ◽  
Geert Jan Biessels
Keyword(s):  
Cognitive Impairment ◽  
High Resolution ◽  
Neuronal Loss ◽  
Weighted Average ◽  
Vascular Cognitive Impairment ◽  
Brain Regions ◽  
Older Individuals ◽  
High Resolution Mri ◽  
Magnetic Resonance Imaging Mri

Vascular cognitive impairment is an umbrella term for cognitive dysfunction associated with and presumed to be caused by vascular brain damage. Autopsy studies have identified microinfarcts as an important neuropathological correlate of vascular cognitive impairment that escapes detection by conventional magnetic resonance imaging (MRI). As a frame of reference for future high-resolution MRI studies, we systematically reviewed the literature on neuropathological studies on cerebral microinfarcts in the context of vascular disease, vascular risk factors, cognitive decline and dementia. We identified 32 original patient studies involving 10,515 people. The overall picture is that microinfarcts are common, particularly in patients with vascular dementia (weighted average 62%), Alzheimer's disease (43%), and demented patients with both Alzheimer-type and cerebrovascular pathology (33%) compared with nondemented older individuals (24%). In many patients, multiple microinfarcts were detected. Microinfarcts are described as minute foci with neuronal loss, gliosis, pallor, or more cystic lesions. They are found in all brain regions, possibly more so in the cerebral cortex, particularly in watershed areas. Reported sizes vary from 50 μm to a few mm, which is within the detection limit of current high-resolution MRI. Detection of these lesions in vivo would have a high potential for future pathophysiological studies in vascular cognitive impairment.

scholarly journals Simultaneous PET/Mri in Stroke: A Case Series

2015 ◽  
Vol 35 (9) ◽  
pp. 1421-1425 ◽  
Author(s):  
Peter Werner ◽  
Dorothee Saur ◽  
Vilia Zeisig ◽  
Barbara Ettrich ◽  
Marianne Patt ◽  
...  
Keyword(s):  
Case Series ◽  
Patient Stratification ◽  
Resonance Imaging ◽  
Ovine Model ◽  
Stroke Patients ◽  
Complementary Information ◽  
Systemic Thrombolysis ◽  
Positron Emission ◽  
Magnetic Resonance Imaging Mri ◽  
Post Hoc

Prospective studies on magnetic resonance imaging (MRI)-guided systemic thrombolysis 44.5 hours after stroke onset did not reach their primary end points. It was discussed and observed in post hoc data re-assessment that this was partly because of limited MRI accuracy to measure critical hypoperfusion. We report the first cases of simultaneous [15O]H2O-positron emission tomography (PET)/MRI in stroke patients and an ovine model. Discrepancies between simultaneously obtained PET and MRI readouts were observed that might explain the above current limitations of stroke MRI. By offering highly complementary information, [15O]H2O-PET/MRI might help to identify critically hypoperfused tissue resulting in an improved patient stratification in thrombolysis trials.

scholarly journals Metabolic Impairment in Human Amnesia: A PET Study of Memory Networks

1992 ◽  
Vol 12 (3) ◽  
pp. 353-358 ◽  
Author(s):  
Ferruccio Fazio ◽  
Daniela Perani ◽  
Maria Carla Gilardi ◽  
Fabio Colombo ◽  
Stefano F. Cappa ◽  
...  
Keyword(s):  
Hippocampal Formation ◽  
Cerebral Metabolism ◽  
Human Memory ◽  
Clinical Syndrome ◽  
Long Term Memory ◽  
Positron Emission ◽  
New Information ◽  
Magnetic Resonance Imaging Mri

Human amnesia is a clinical syndrome exhibiting the failure to recall past events and to learn new information. Its “pure” form, characterized by a selective impairment of long-term memory without any disorder of general intelligence or other cognitive functions, has been associated with lesions localized within Papez's circuit and some connected areas. Thus, amnesia could be due to a functional disconnection between components of this or other neural structures involved in long-term learning and retention. To test this hypothesis, we measured regional cerebral metabolism with 2-[18F]fluoro-2-deoxy-d-glucose ([18F]FDG) and positron emission tomography (PET) in 11 patients with “pure” amnesia. A significant bilateral reduction in metabolism in a number of interconnected cerebral regions (hippocampal formation, thalamus, cingulate gyrus, and frontal basal cortex) was found in the amnesic patients in comparison with normal controls. The metabolic impairment did not correspond to alterations in structural anatomy as assessed by magnetic resonance imaging (MRI). These results are the first in vivo evidence for the role of a functional network as a basis of human memory.

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