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11C-PBR28 imaging in multiple sclerosis patients and healthy controls: test-retest reproducibility and focal visualization of active white matter areas

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Abstract

Purpose

Activated microglia play a key role in inflammatory demyelinating injury in multiple sclerosis (MS). Microglial activation can be measured in vivo using a positron emission tomography (PET) ligand 11C-PBR28. We evaluated the test-retest variability (TRV) and lesion detectability of 11C-PBR28 binding in MS subjects and healthy controls (HCs) with high-resolution PET.

Methods

Four clinically and radiologically stable relapsing-remitting MS subjects (age 41 ± 7 years, two men/two women) and four HCs (age 42 ± 8 years, 2 two men/two women), matched for translocator protein genotype [two high- and two medium-affinity binders according to DNA polymorphism (rs6971) in each group], were studied for TRV. Another MS subject (age 41 years, male) with clinical and radiological activity was studied for lesion detectability. Dynamic data were acquired over 120 min after injection of 634 ± 101 MBq 11C-PBR28. For the TRV study, subjects were scanned twice, on average 1.4 weeks apart. Volume of distribution (V T) derived from multilinear analysis (MA1) modeling (t* = 30 min, using arterial input data) was the main outcome measure.

Results

Mean test V T values (ml cm−3) were 3.9 ± 1.4 in the whole brain gray matter (GM), 3.6 ± 1.2 in the whole brain white matter (WM) or normal-appearing white matter (NAWM), and 3.3 ± 0.6 in MS WM lesions; mean retest V T values were 3.7 ± 1.0 in GM, 3.3 ± 0.9 in WM/NAWM, and 3.3 ± 0.7 in MS lesions. Test-retest results showed a mean absolute TRV ranging from 7 to 9 % across GM, WM/NAWM, and MS lesions. High-affinity binders demonstrated 30 % higher V T than medium-affinity binders in GM. Focal 11C-PBR28 uptake was detected in two enhancing lesions of the active MS patient.

Conclusion

High-resolution 11C-PBR28 PET can visualize focal areas where microglial activation is known to be present and has good test-retest reproducibility in the human brain. 11C-PBR28 PET is likely to be valuable for monitoring both MS disease evolution and response to therapeutic strategies that target microglial activation.

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Acknowledgments

We thank the staff at Yale PET Center, Yale-New Haven Hospital, and Yale MR Research Center. This study was supported by F. Hoffmann-La Roche Ltd and SNMMI research grant for junior medical faculty.

Compliance with ethical standards

ᅟ

Conflicts of interest

Kevin C. O’Connor has received speaker honoraria from EMD-Serono. Nicholas Seneca and David Leppert are currently employees of Hoffmann-La Roche Ltd. Daniel Pelletier received consulting honoraria from CNS Imaging Consultant, LLC. Eunkyung Park, Jean-Dominique Gallezot, Aracely Delgadillo, Shuang Liu, Beata Planeta, Shu-Fei Lin, Keunpoong Lim, Jae-Yun Lee, Anne Chastre, Ming-Kai Chen, Yiyun Huang, and Richard E. Carson have no conflict of interest relevant to this article.

Research involving human participants

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Authors and Affiliations

  1. PET Center, Department of Diagnostic Radiology, Yale School of Medicine, 801 Howard Avenue, PO Box 208048, New Haven, CT, 06520-8048, USA

    Eunkyung Park, Jean-Dominique Gallezot, Beata Planeta, Shu-Fei Lin, Keunpoong Lim, Ming-Kai Chen, Yiyun Huang & Richard E. Carson

  2. Department of Neurology, Yale School of Medicine, New Haven, CT, USA

    Aracely Delgadillo, Shuang Liu, Kevin C. O’Connor, Jae-Yun Lee, Anne Chastre & Daniel Pelletier

  3. Pharmaceuticals Division, Hoffmann-La Roche Ltd, Basel, Switzerland

    Nicholas Seneca & David Leppert

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  1. Eunkyung Park
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  2. Jean-Dominique Gallezot
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Correspondence to Eunkyung Park.

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Park, E., Gallezot, JD., Delgadillo, A. et al. 11C-PBR28 imaging in multiple sclerosis patients and healthy controls: test-retest reproducibility and focal visualization of active white matter areas. Eur J Nucl Med Mol Imaging 42, 1081–1092 (2015). https://doi.org/10.1007/s00259-015-3043-4

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