Characterization of age/sex and the regional distribution of mGluR5 availability in the healthy human brain measured by high-resolution [11C]ABP688 PET
Metabotropic glutamate receptor type 5 (mGluR5) is a G protein-coupled receptor that has been implicated in several psychiatric and neurological diseases. The radiopharmaceutical [11C]ABP688 allows for in vivo quantification of mGluR5 availability using positron emission tomography (PET). In this study, we aimed to detail the regional distribution of [11C]ABP688 binding potential (BPND) and the existence of age/sex effects in healthy individuals.
Thirty-one healthy individuals aged 20 to 77 years (men, n = 18, 45.3 ± 18.2 years; females, n = 13, 41.5 ± 19.6 years) underwent imaging with [11C]ABP688 using the high-resolution research tomograph (HRRT). We developed an advanced partial volume correction (PVC) method using surface-based analysis in order to accurately estimate the regional variation of radioactivity. BPND was calculated using the simplified reference tissue model, with the cerebellum as the reference region. Surface-based and volume-based analyses were performed for 39 cortical and subcortical regions of interest per hemisphere.
We found the highest [11C]ABP688 BPND in the lateral prefrontal and anterior cingulate cortices. The lowest [11C]ABP688 BPND was observed in the pre- and post-central gyri as well as the occipital lobes and the thalami. No sex effect was observed. Associations between age and [11C]ABP688 BPND without PVC were observed in the right amygdala and left putamen, but were not significant after multiple comparisons correction.
The present results highlight complexities underlying brain adaptations during the aging process, and support the notion that certain aspects of neurotransmission remain stable during the adult life span.
KeywordsHealthy controls Positron emission tomography [11C]ABP688 Metabotropic glutamate receptor 5
Compliance with Ethical Standards
The study was funded by the Savoy Foundation for Epilepsy (www.savoy-foundation.ca) (pilot project grant to EK and PRN and PhD studentship to JMD), and partially by the American Epilepsy Society (www.aesnet.org) (Early Career Physician Scientist Award to EK), Canadian Institutes of Health Research (CIHR) (www.cihr-irsc.gc.ca) [MOP-115131 to PRN and MOP-93614 to EK], and the Fonds de la recherche en santé du Québec (www.frqs.gouv.qc.ca) (PRN, research fellow).
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the Montreal Neurological Institute Research Ethics Board and the institutional review board of McGill University, and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.
Informed consent was obtained from all individual participants included in the study.
- 26.Comtat C, Sureau F, Sibomana M, Hong I, Sjöholm N, Trebossen R. Image based resolution modeling for the HRRT OSEM reconstructions software. IEEE Nucl Sci Symp Conf Rec. 2008;4120–23.Google Scholar
- 31.Milella M, Reader A, Albrechtsons D, Minuzi L, Soucy J, Benkelfat C. Human PET validation study of reference tissue models for the mGluR5 ligand [11C] ABP688. Paper presented at Society for Neuroscience Annual Meeting. Washington, DC; 2011. 946.06/AAA31.Google Scholar
- 46.Benjamini Y, Hochberg Y. Controlling the False Discovery Rate: a Practical and Powerful Approach to Multiple Testing. J R Stat Soc. 1995;57(1):289–300.Google Scholar
- 47.R Development Core Team. R: a language and environment for statistical computing. 2013. http://www.R-project.org/.
- 48.Tukey JW. Exploratory data analysis. Reading, MA: Addison-Wesley; 1977.Google Scholar
- 59.Car H, Stefaniuk R, Wiśniewska R. Effect of MPEP in Morris water maze in adult and old rats. Pharmacol Rep. 2006;59(1):88–93.Google Scholar
- 60.Leuzy A, Zimmer ER, Dubois J, Pruessner J, Cooperman C, Soucy JP, et al. In vivo characterization of metabotropic glutamate receptor type 5 abnormalities in behavioral variant FTD. Brain Struct Funct. 2015. doi: 10.1007/s00429-014-0978-3.
- 63.DeLorenzo C, Milak MS, Brennan KG, Kumar JS, Mann JJ, Parsey RV. In vivo positron emission tomography imaging with [(1)(1)C]ABP688: binding variability and specificity for the metabotropic glutamate receptor subtype 5 in baboons. Eur J Nucl Med Mol Imaging. 2011;38(6):1083–94.PubMedCentralCrossRefPubMedGoogle Scholar
- 64.Mathews WB, Kuwabara H, Stansfield K, Valentine H, Alexander M, Kumar A, et al. Dose-dependent, saturable occupancy of the metabotropic glutamate subtype 5 receptor by fenobam as measured with [11C] ABP688 PET imaging. Synapse. 2014;68(12):565–73.Google Scholar
- 67.DeLorenzo C, DellaGioia N, Bloch M, Sanacora G, Nabulsi N, Abdallah C, et al. In vivo ketamine-induced changes in [11C]ABP688 binding to metabotropic glutamate receptors subtype 5. Biol Psychiatry. 2015;77(3):266–75.Google Scholar
- 68.Wyckhuys T, Verhaeghe J, Wyffels L, Langlois X, Schmidt M, Stroobants S, et al. N-acetylcysteine- and MK-801-induced changes in glutamate levels do not affect in vivo binding of metabotropic glutamate 5 receptor radioligand 11C-ABP688 in rat brain. J Nucl Med. 2013;54(11):1954–61.CrossRefPubMedGoogle Scholar
- 69.Zimmer ER, Parent MJ, Leuzy A, Aliaga A, Aliaga A, Moquin L, et al. Imaging in vivo glutamate fluctuations with [C]ABP688: a GLT-1 challenge with ceftriaxone. J Cereb Blood Flow Metab. 2015;35:1169–74.Google Scholar