Dynamic TSPO-PET for assessing early effects of cerebral hypoxia and resuscitation in new born pigs

Lange, Charlotte de; Solberg, Rønnaug; Holtedahl, Jon Erik; Tulipan, Andreas Julius; Barlinn, Jon; Trigg, William; Wickstrøm, Torild; Saugstad, Ola Didrik; Malinen, Eirik; Revheim, Mona-Elisabeth

doi:10.1016/j.nucmedbio.2018.08.004

Cited by 6 publications

(3 citation statements)

References 51 publications

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“…While leading to a pronounced increase in VT, administration of lipopolysaccharide had no apparent effect on SIME VND. Lipopolysaccharide is a useful model to study an acute immune response, and upregulation of TSPO has been observed in vivo in several species, including mice (13), rats (14), pigs (15) and non-human primates (16). When using VS as outcome measure, we observe a larger percentage separation between the pre-and post-lipopolysaccharide scans, with mean percentage differences of 59% and 66% in cerebellum and frontal cortex respectively, and with similar variability as VT (coefficient of variation, SD/mean, were 0.85 for VT and 0.86 for VS).…”

Section: Lipopolysaccharidementioning

confidence: 99%

Nondisplaceable Binding Is a Potential Confounding Factor in ¹¹C-PBR28 Translocator Protein PET Studies

et al. 2020

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The positron emission tomography (PET) ligand 11 C-PBR28 binds to the 18kDa translocator protein (TSPO), a biomarker of glia. In clinical studies of TSPO, the ligand total distribution volume, VT, is frequently the reported outcome measure. Since VT is the sum of the ligand specific (VS) and non-displaceable binding (VND), differences in VND across subjects and groups will have an impact on VT.Methods: Here, we used a recently developed method for simultaneous estimation of VND (SIME) to disentangle contributions from VND and VS. Data from four previously published 11 C-PBR28 PET studies were included: (i) before and after a lipopolysaccharide challenge (8 subjects), (ii) in alcohol use disorder (14 patients, 15 controls), (iii) in first-episode psychosis ( 16patients, 16 controls), and (iv) in Parkinson's disease (16 patients, 16 controls). In each dataset, regional VT estimates were obtained with a standard two-tissue compartment model, and brainwide VND was estimated with SIME. VS was then calculated as VT-VND. VND and VS were then compared across groups, within each dataset.Results: A lower VND was found for individuals with alcohol use disorder (34%, p=0.00084) and Parkinson's disease (34%, p=0.0032), when compared to their corresponding controls. We found no difference in VND between first-episode psychosis patients and their controls, and the administration of lipopolysaccharide did not change VND. Conclusion:Our findings suggest that in TSPO PET studies, non-displaceable binding can differ between patient groups and conditions and should therefore be taken into account.

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Section: Lipopolysaccharidementioning

confidence: 99%

Nondisplaceable Binding Is a Potential Confounding Factor in ¹¹C-PBR28 Translocator Protein PET Studies

et al. 2020

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“…Pigs are very similar to humans on a genetic, brain developmental, physiological, and organic level. This evolutionary relationship further encompasses the genetic diversity among individuals, which is reflected in the variation in expression patterns [ 61 , 62 ]. The observed variations are methodologically challenging for molecular biology research, requiring a large number of individuals and study areas to keep the SD low; however, they more realistically reflect the actual situation we face in birth asphyxia in the clinic.…”

Section: Discussionmentioning

confidence: 99%

Long Non-Coding RNAs in Hypoxia and Oxidative Stress: Novel Insights Investigating a Piglet Model of Perinatal Asphyxia

Tune

Melheim

Åsegg-Atneosen

et al. 2023

Biology

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Birth asphyxia is the leading cause of death and disability in young children worldwide. Long non-coding RNAs (lncRNAs) may provide novel targets and intervention strategies due to their regulatory potential, as demonstrated in various diseases and conditions. We investigated cardinal lncRNAs involved in oxidative stress, hypoxia, apoptosis, and DNA damage using a piglet model of perinatal asphyxia. A total of 42 newborn piglets were randomized into 4 study arms: (1) hypoxia–normoxic reoxygenation, (2) hypoxia–3 min of hyperoxic reoxygenation, (3) hypoxia–30 min of hyperoxic reoxygenation, and (4) sham-operated controls. The expression of lncRNAs BDNF-AS, H19, MALAT1, ANRIL, TUG1, and PANDA, together with the related target genes VEGFA, BDNF, TP53, HIF1α, and TNFα, was assessed in the cortex, the hippocampus, the white matter, and the cerebellum using qPCR and Droplet Digital PCR. Exposure to hypoxia–reoxygenation significantly altered the transcription levels of BDNF-AS, H19, MALAT1, and ANRIL. BDNF-AS levels were significantly enhanced after both hypoxia and subsequent hyperoxic reoxygenation, 8% and 100% O2, respectively. Our observations suggest an emerging role for lncRNAs as part of the molecular response to hypoxia-induced damages during perinatal asphyxia. A better understanding of the regulatory properties of BDNF-AS and other lncRNAs may reveal novel targets and intervention strategies in the future.

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“…In that perspective, some studies used TSPO-PET imaging to better characterize the temporal and anatomical evolution of neuroinflammation in various models of experimental stroke, some of them new. De Lange et al [ 81 ] used [ 18 F]GE-180 to evaluate acute neuroinflammation in a model of hypoxia resuscitation in newborn piglets. Considering the numerous reports showing that it takes approximately 3 days for microglia to proliferate and TSPO expression to increase in stroke and LPS model of neuroinflammation, unsurprisingly this study did not detect any significant change in [ 18 F]GE-180 between 5 and 32 h post-hypoxia.…”

Section: Models Of Acute Neuroinflammationmentioning

confidence: 99%

TSPO imaging in animal models of brain diseases

Camp

Lavisse

Roost

et al. 2021

Eur J Nucl Med Mol Imaging

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Over the last 30 years, the 18-kDa TSPO protein has been considered as the PET imaging biomarker of reference to measure increased neuroinflammation. Generally assumed to image activated microglia, TSPO has also been detected in endothelial cells and activated astrocytes. Here, we provide an exhaustive overview of the recent literature on the TSPO-PET imaging (i) in the search and development of new TSPO tracers and (ii) in the understanding of acute and chronic neuroinflammation in animal models of neurological disorders. Generally, studies testing new TSPO radiotracers against the prototypic [11C]-R-PK11195 or more recent competitors use models of acute focal neuroinflammation (e.g. stroke or lipopolysaccharide injection). These studies have led to the development of over 60 new tracers during the last 15 years. These studies highlighted that interpretation of TSPO-PET is easier in acute models of focal lesions, whereas in chronic models with lower or diffuse microglial activation, such as models of Alzheimer’s disease or Parkinson’s disease, TSPO quantification for detection of neuroinflammation is more challenging, mirroring what is observed in clinic. Moreover, technical limitations of preclinical scanners provide a drawback when studying modest neuroinflammation in small brains (e.g. in mice). Overall, this review underlines the value of TSPO imaging to study the time course or response to treatment of neuroinflammation in acute or chronic models of diseases. As such, TSPO remains the gold standard biomarker reference for neuroinflammation, waiting for new radioligands for other, more specific targets for neuroinflammatory processes and/or immune cells to emerge.

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Dynamic TSPO-PET for assessing early effects of cerebral hypoxia and resuscitation in new born pigs

Cited by 6 publications

References 51 publications

Nondisplaceable Binding Is a Potential Confounding Factor in ¹¹C-PBR28 Translocator Protein PET Studies

Nondisplaceable Binding Is a Potential Confounding Factor in ¹¹C-PBR28 Translocator Protein PET Studies

Long Non-Coding RNAs in Hypoxia and Oxidative Stress: Novel Insights Investigating a Piglet Model of Perinatal Asphyxia

TSPO imaging in animal models of brain diseases

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Dynamic TSPO-PET for assessing early effects of cerebral hypoxia and resuscitation in new born pigs

Cited by 6 publications

References 51 publications

Nondisplaceable Binding Is a Potential Confounding Factor in 11C-PBR28 Translocator Protein PET Studies

Nondisplaceable Binding Is a Potential Confounding Factor in 11C-PBR28 Translocator Protein PET Studies

Long Non-Coding RNAs in Hypoxia and Oxidative Stress: Novel Insights Investigating a Piglet Model of Perinatal Asphyxia

TSPO imaging in animal models of brain diseases

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Nondisplaceable Binding Is a Potential Confounding Factor in ¹¹C-PBR28 Translocator Protein PET Studies

Nondisplaceable Binding Is a Potential Confounding Factor in ¹¹C-PBR28 Translocator Protein PET Studies