Microglial imaging with positron emission tomography and atrophy measurements                 with magnetic resonance imaging in multiple sclerosis: a correlative study

Versijpt, Jan; Debruyne, Jan; Laere, KJ Van; Vos, Filip De; Keppens, Johan; Strijckmans, Karel; Achten, Eric; Slegers, Guido; Dierckx, Rudi; Korf, Jakob; Reuck, J. De

doi:10.1191/1352458505ms1140oa

Cited by 114 publications

(91 citation statements)

References 59 publications

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“…One early study suggested the presence of focal areas of increased uptake in normal-appearing white (and gray) matter (8). However, patterns of ligand uptake in T2-weighted hyperintensities and correlations between 11 C-(R)-PK11195 uptake and disease duration and disability have been inconsistent in previous studies (8,10,33). This inconsistency could reflect differences in patient populations, differences in the proportion of specific (displaceable) signal between 18 F-PBR111 and 11 C-(R)-PK11195, or accurate modeling, which is particularly challenging for the lower-affinity 11 C-(R)-PK11195 (24,34).…”

Section: Discussionmentioning

confidence: 99%

In Vivo Assessment of Brain White Matter Inflammation in Multiple Sclerosis with¹⁸F-PBR111 PET

et al. 2014

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PET radioligand binding to the 18-kD translocator protein (TSPO) in the brains of patients with multiple sclerosis (MS) primarily reflects activated microglia and macrophages. We previously developed genetic stratification for accurate quantitative estimation of TSPO using second-generation PET radioligands. In this study, we used 18 F-PBR111 PET and MR imaging to measure relative binding in the lesional, perilesional, and surrounding normal-appearing white matter of MS patients, as an index of the innate immune response. Methods: 18 F-PBR111 binding was quantified in 11 MS patients and 11 age-matched healthy volunteers, stratified according to the rs6971 TSPO gene polymorphism. Fluid-attenuated inversion recovery and magnetization transfer ratio (MTR) MR imaging were used to segment the white matter in MS patients as lesions, perilesional volumes, nonlesional white matter with reduced MTR, and nonlesional white matter with normal MTR. Results: 18 F-PBR111 binding was higher in the white matter lesions and perilesional volumes of MS patients than in white matter of healthy controls (P , 0.05). Although there was substantial heterogeneity in binding between different lesions, a within-subject analysis showed higher 18 F-PBR111 binding in MS lesions (P , 0.05) and in perilesional (P , 0.05) and nonlesional white matter with reduced MTR (P , 0.005) than in nonlesional white matter with a normal MTR. A positive correlation was observed between the mean 18 F-PBR111 volume of distribution increase in lesions relative to nonlesional white matter with a normal MTR and the MS severity score (Spearman ρ 5 0.62, P , 0.05). Conclusion: This study demonstrates that quantitative TSPO PET with a second-generation radioligand can be used to characterize innate immune responses in MS in vivo and provides further evidence supporting an association between the white matter TSPO PET signal in lesions and disease severity. Our approach is practical for extension to studies of the role of the innate immune response in MS for differentiation of antiinflammatory effects of new medicines and their longer term impact on clinical outcome.

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Section: Discussionmentioning

confidence: 99%

In Vivo Assessment of Brain White Matter Inflammation in Multiple Sclerosis with¹⁸F-PBR111 PET

et al. 2014

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“…Both [ 11 C](R)-PK11195 and [ 11 C]PK11195 have been used as positron emmision tomography (PET) tracers to study activated microglia in various neurologic disorders. It has been used to study stroke (Ramsay et al, 1992;Pappata et al, 2000;Gerhard et al, 2000Gerhard et al, , 2005a), Alzheimer's disease (Groom et al, 1995; Cagnin et al, 2001a;Versijpt et al, 2003), multiple sclerosis (Banati et al, 2000;Debruyne et al, 2002Debruyne et al, , 2003Versijpt et al, 2005) and various other diseases (Pappata et al, 1991; Banati et al, 1999Banati et al, , 2001Goerres et al, 2001;Cagnin et al, 2001bCagnin et al, , 2004Cicchetti et al, 2002;Gerhard et al, 2003Gerhard et al, , 2004Gerhard et al, , 2005bTurner et al, 2004Turner et al, , 2005Venneti et al, 2004;Henkel et al, 2004;Ouchi et al, 2005). Most studies have used a reference tissue approach to quantify binding, either by applying the simplified reference tissue model (SRTM) (Lammertsma and Hume, 1996) or by using uptake normalized to a reference region.…”

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confidence: 99%

Evaluation of Reference Tissue Models for the Analysis of [¹¹C](R)-PK11195 Studies

Kropholler

Boellaard

Schuitemaker

et al. 2006

J Cereb Blood Flow Metab

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[ 11 C](R)-PK11195 is a marker of activated microglia, which can be used to measure inflammation in neurologic disorders. The purpose of the present study was to define the optimal reference tissue model based on a comparison with a validated plasma input model and using clinical studies and Monte Carlo simulations. Accuracy and reproducibility of reference tissue models were evaluated using Monte Carlo simulations. The effects of noise and variation in specific binding, nonspecific binding and blood volume were evaluated. Dynamic positron emission tomography scans were performed on 13 subjects, and radioactivity in arterial blood was monitored online. In addition, blood samples were taken to generate a metabolite corrected plasma input function. Both a (validated) two-tissue reversible compartment model with K 1 /k 2 fixed to whole cortex and various reference tissue models were fitted to the data. Finally, a simplified reference tissue model (SRTM) corrected for nonspecific binding using plasma input data (SRTM pl_corr ) was investigated. Correlations between reference tissue models (including SRTM pl_corr ) and the plasma input model were calculated. Monte Carlo simulations indicated that low-specific binding results in decreased accuracy and reproducibility. In this respect, the SRTM and SRTM pl_corr performed relatively well. Varying blood volume had no effect on performance. In the clinical evaluation, SRTM pl_corr and SRTM had the highest correlations with the plasma input model (R 2 = 0.82 and 0.78, respectively). SRTM pl_corr is optimal when an arterial plasma input curve is available. Simplified reference tissue model is the best alternative when no plasma input is available. Keywords: microglia; peripheral benzodiazepine receptor; PET (positron emission tomography); PK11195; reference tissue models; tracer kinetic modelling IntroductionCarbon-11 labeled (R)-PK11195 ((R)-1-(2-chlorophenyl)-N-[ 11 C]methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide) is a ligand for the peripheral benzodiazepine receptor. In the brain, this receptor is mainly expressed on activated microglia (Banati et al, 1997). Both [ 11 C](R)-PK11195 and [ 11 C]PK11195 have been used as positron emmision tomography (PET) tracers to study activated microglia in various neurologic disorders. It has been used to study stroke (Ramsay et al, 1992;Pappata et al, 2000;Gerhard et al, 2000Gerhard et al, , 2005a), Alzheimer's disease (Groom et al, 1995; Cagnin et al, 2001a;Versijpt et al, 2003), multiple sclerosis (Banati et al, 2000;Debruyne et al, 2002Debruyne et al, , 2003Versijpt et al, 2005) and various other diseases (Pappata et al, 1991; Banati et al, 1999Banati et al, , 2001Goerres et al, 2001;Cagnin et al, 2001bCagnin et al, , 2004Cicchetti et al, 2002;Gerhard et al, 2003Gerhard et al, , 2004Gerhard et al, , 2005bTurner et al, 2004Turner et al, , 2005Venneti et al, 2004;Henkel et al, 2004;Ouchi et al, 2005). Most studies have used a reference tissue approach to quantify binding, either by applying the simplified reference tissue mod...

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“…In the brain, (R)- [ 11 C]PK11195 binds to activated microglia [7] which are part of the brain's immune system. (R)- [ 11 C] PK11195 has been used extensively to image brain inflammation using PET [8][9][10][11][12][13][14][15][16]. Methods have been published regarding the quantification of (R)- [ 11 C] PK11195 binding in the brain [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Quantification of (R)-[11C]PK11195 binding in rheumatoid arthritis

Kropholler

Boellaard

Elzinga

et al. 2008

Eur J Nucl Med Mol Imaging

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Purpose Rheumatoid arthritis (RA) involves migration of macrophages into inflamed areas. (R)-[11 C]PK11195 binds to peripheral benzodiazepine receptors, expressed on macrophages, and may be used to quantify inflammation using positron emission tomography (PET). This study evaluated methods for the quantification of (R)- Conclusion (R)-[11 C]PK11195 kinetics in the knee were best described by a reversible single-tissue compartment model including blood volume. Applying metabolite corrections did not increase sensitivity. Due to the high correlation with V d , SUV is a practical alternative for clinical use.

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Microglial imaging with positron emission tomography and atrophy measurements with magnetic resonance imaging in multiple sclerosis: a correlative study

Abstract: The present study suggests that brain atrophy, correlating with disease duration and disability, is directly related to NAWM and T2-lesional inflammation as measured by microglial activation.

Cited by 114 publications

References 59 publications

In Vivo Assessment of Brain White Matter Inflammation in Multiple Sclerosis with¹⁸F-PBR111 PET

In Vivo Assessment of Brain White Matter Inflammation in Multiple Sclerosis with¹⁸F-PBR111 PET

Evaluation of Reference Tissue Models for the Analysis of [¹¹C](R)-PK11195 Studies

Quantification of (R)-[11C]PK11195 binding in rheumatoid arthritis

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Microglial imaging with positron emission tomography and atrophy measurements with magnetic resonance imaging in multiple sclerosis: a correlative study

Abstract: The present study suggests that brain atrophy, correlating with disease duration and disability, is directly related to NAWM and T2-lesional inflammation as measured by microglial activation.

Cited by 114 publications

References 59 publications

In Vivo Assessment of Brain White Matter Inflammation in Multiple Sclerosis with18F-PBR111 PET

In Vivo Assessment of Brain White Matter Inflammation in Multiple Sclerosis with18F-PBR111 PET

Evaluation of Reference Tissue Models for the Analysis of [11C](R)-PK11195 Studies

Quantification of (R)-[11C]PK11195 binding in rheumatoid arthritis

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Product

Resources

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In Vivo Assessment of Brain White Matter Inflammation in Multiple Sclerosis with¹⁸F-PBR111 PET

In Vivo Assessment of Brain White Matter Inflammation in Multiple Sclerosis with¹⁸F-PBR111 PET

Evaluation of Reference Tissue Models for the Analysis of [¹¹C](R)-PK11195 Studies