Voxel-Based Imaging of Translocator Protein 18Kda (TSPO) in High-Resolution PET

Ko, Ji Hyun; Koshimori, Yuko; Mizrahi, Romina; Rusjan, Pablo; Wilson, Alan A.; Lang, Anthony E.; Houle, Sylvain; Strafella, Antonio P.

doi:10.1038/jcbfm.2012.203

Cited by 10 publications

(11 citation statements)

References 15 publications

(46 reference statements)

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“…After removing the outlier, a similar sample size calculation revealed that to detect a significant effect of diagnostic group in the DLPFC (effect size = 0.26) or hippocampus (effect size = 0.58), we would need, respectively, 231 or 49 participants per group. Despite this variability, the binding of [ 18 F]FEPPA was increased during induced inflammation in animals (Zhang et al, 2012), Major Depressive Episode (MDE) patients (Setiawan et al, 2015), meningioma (Ko et al, 2013), and also Alzheimer's disease in humans (Kreisl et al, 2013b;Suridjan et al, 2015;Yasuno et al, 2008). Also, in this study we did not correct V T for the plasma free fraction of the radioligand (f p ), as it was previously shown to substantially increase the variability (Hines et al, 2013).…”

Section: Discussionmentioning

confidence: 90%

Imaging Microglial Activation in Individuals at Clinical High Risk for Psychosis: an In Vivo PET Study with [18F]FEPPA

Hafizi

Silva

Gerritsen

et al. 2017

Neuropsychopharmacol.

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Several lines of evidence implicate microglial activation and abnormal immune response in the etiology of psychosis. Previous positron emission tomography (PET) neuroimaging studies of the translocator protein 18 kDa, TSPO, were limited by low affinity of the first-generation radioligand, low-resolution scanners, and small sample sizes. Moreover, there is a dearth of literature on microglial activation in individuals at clinical high risk (CHR) for psychosis. We used a novel second-generation TSPO radioligand, [F]FEPPA, to examine whether microglial activation is elevated in the dorsolateral prefrontal cortex (DLPFC) and hippocampus of antipsychotic-naive CHR. Twenty-four CHR (antipsychotic-naive n=22) and 23 healthy volunteers (HV) completed a high resolution [F]FEPPA PET scan and MRI. The PET data were analyzed using the validated two-tissue compartment model with arterial plasma input function with total volume of distribution (V) as outcome measure. All analyses were controlled for the TSPO rs6971 polymorphism. We did not observe any significant differences in microglial activation, as indexed by [F]FEPPA V, between CHR and HV in either the DLPFC (F=0.41, p=0.52) or the hippocampus (F=2.78, p=0.10). Exploratory associations show that in CHR, [F]FEPPA V was positively correlated with apathy (DLPFC: r=0.55, p=0.008; hippocampus: r=0.52, p=0.013) and state anxiety (DLPFC: r=0.60, p=0.003; hippocampus: r=0.48, p=0.024). The lack of significant group differences in [F]FEPPA V suggests that microglial activation is not significantly elevated in the clinical high risk state that precedes psychosis.

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Section: Discussionmentioning

confidence: 90%

Imaging Microglial Activation in Individuals at Clinical High Risk for Psychosis: an In Vivo PET Study with [18F]FEPPA

Hafizi

Silva

Gerritsen

et al. 2017

Neuropsychopharmacol.

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“…Specifically, [ 18 F]-FEPPA displayed a similar uptake to that of [ 11 C]-PK11195 in the lesioned area, but showed lower uptake in the healthy area, demonstrating the specificity of [ 18 F]-FEPPA binding towards TSPO-enriched lesions (Hatano et al, 2010). More recently, (Ko et al, 2013) showed that [ 18 F]-FEPPA uptake was three-fold higher at the tumor site compared to the contralateral side. Further, inter-individual variability in binding affinity was observed in second-generation TSPO ligands, but not with [ 11 ]-PK11195, suggesting that [ 11 ]-PK11195 may bind to a different site of TSPO (Kreisl et al, 2010; Owen et al, 2010, 2011).…”

Section: Discussionmentioning

confidence: 99%

Neuroinflammation in healthy aging: A PET study using a novel Translocator Protein 18kDa (TSPO) radioligand, [18F]-FEPPA

et al. 2014

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One of the cellular markers of neuroinflammation is increased microglia activation, characterized by overexpression of mitochondrial 18 kDa Translocator Protein (TSPO). TSPO expression can be quantified in-vivo using the positron emission tomography (PET) radioligand [18F]-FEPPA. This study examined microglial activation as measured with [18F]-FEPPA PET across the adult lifespan in a group of healthy volunteers. We performed genotyping for the rs6971 TS.PO gene polymorphism to control for the known variability in binding affinity. Thirty-three healthy volunteers (age range: 19–82 years; 22 high affinity binders (HAB), 11 mixed affinity binders (MAB)) underwent [18F]-FEPPA PET scans, acquired on the High Resolution Research Tomograph (HRRT) and analyzed using a 2-tissue compartment model. Regression analyses were performed to examine the effect of age adjusting for genetic status on [18F]-FEPPA total distribution volumes (VT) in the hippocampus, temporal, and prefrontal cortex. We found no significant effect of age on [18F]-FEPPA VT (F (1,30) = 0.918; p = 0.346), and a significant effect of genetic polymorphism (F (1,30) = 8.767; p = 0.006). This is the first in-vivo study to evaluate age-related changes in TSPO binding, using the new generation TSPO radioligands. Increased neuroinflammation, as measured with [18F]-FEPPA PET was not associated with normal aging, suggesting that healthy elderly individuals may serve as useful benchmark against patients with neurodegenerative disorders where neuroinflammation may be present.

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“…clinically or pharmacologically meaningful, the dynamic range of the measure and its test--retest variability. As noted above, under some conditions, TSPO binding reflects astroglial activation (or transformation in malignant gliomas [63]). Other radioligands described below are becoming available that promise to distinguish astrocytic from microglial activation.…”

Section: Molecular Imaging Of Astrocyte Activationmentioning

confidence: 92%

Positron-emission tomography molecular imaging of glia and myelin in drug discovery for multiple sclerosis

Matthews

Datta

2015

Expert Opinion on Drug Discovery

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Strengths of PET lie in the molecular selectivity, sensitivity and potential for absolute quantitation. Even now, translocator protein PET radioligands could be used in exploratory studies for interventions targeting brain microglial activation. The clinical and neuropathological meaningfulness of signal from PET radioligands reporting on astrocyte activation through cellular expression of either monoamine oxidase B or the I2-imidazoline receptor or metabolism of [(11)C]acetate can now explored. [(11)C] N-methyl-4,4'-diaminostilbene, a PET marker for myelin, could soon enter first human trials. However, use of any of these PET glial markers demands a well-focused hypothesis and a commitment to validation in the context of use. Enhanced access to these radioligands, standardisation of analyses and lowering the costs of using them are needed if their full promise is to be realised.

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Voxel-Based Imaging of Translocator Protein 18Kda (TSPO) in High-Resolution PET

Cited by 10 publications

References 15 publications

Imaging Microglial Activation in Individuals at Clinical High Risk for Psychosis: an In Vivo PET Study with [18F]FEPPA

Imaging Microglial Activation in Individuals at Clinical High Risk for Psychosis: an In Vivo PET Study with [18F]FEPPA

Neuroinflammation in healthy aging: A PET study using a novel Translocator Protein 18kDa (TSPO) radioligand, [18F]-FEPPA

Positron-emission tomography molecular imaging of glia and myelin in drug discovery for multiple sclerosis

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