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The regional pattern of age-related synaptic loss in the human brain differs from gray matter volume loss: in vivo PET measurement with [11C]UCB-J

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Abstract

Purpose

Aging is a major societal concern due to age-related functional losses. Synapses are crucial components of neural circuits, and synaptic density could be a sensitive biomarker to evaluate brain function. [11C]UCB-J is a positron emission tomography (PET) ligand targeting synaptic vesicle glycoprotein 2A (SV2A), which can be used to evaluate brain synaptic density in vivo.

Methods

We evaluated age-related changes in gray matter synaptic density, volume, and blood flow using [11C]UCB-J PET and magnetic resonance imaging (MRI) in a wide age range of 80 cognitive normal subjects (21–83 years old). Partial volume correction was applied to the PET data.

Results

Significant age-related decreases were found in 13, two, and nine brain regions for volume, synaptic density, and blood flow, respectively. The prefrontal cortex showed the largest volume decline (4.9% reduction per decade: RPD), while the synaptic density loss was largest in the caudate (3.6% RPD) and medial occipital cortex (3.4% RPD). The reductions in caudate are consistent with previous SV2A PET studies and likely reflect that caudate is the site of nerve terminals for multiple major tracts that undergo substantial age-related neurodegeneration. There was a non-significant negative relationship between volume and synaptic density reductions in 16 gray matter regions.

Conclusion

MRI and [11]C-UCB-J PET showed age-related decreases of gray matter volume, synaptic density, and blood flow; however, the regional patterns of the reductions in volume and SV2A binding were different. Those patterns suggest that MR-based measures of GM volume may not be directly representative of synaptic density.

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Acknowledgements

We deeply thank all the staff of the Yale PET Center for their expert assistance.

Funding

This study was supported by grants UL1 TR000142 from the National Center for Advancing Translational Sciences (NCATS), and T32GM136651 from the National Institute of General Medical Sciences, components of the National Institutes of Health (NIH).

Author information

Author notes

  1. Irina Esterlis

    Present address: PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, 06520, USA

Authors and Affiliations

  1. PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, 06520, USA

    Takuya Toyonaga, Nikkita Khattar, Yanjun Wu, Yihuan Lu, Mika Naganawa, Jean-Dominique Gallezot, David Matuskey, Mark Dias, Nabeel B. Nabulsi, Sjoerd J. Finnema, Ming-Kai Chen, Yiyun Huang & Richard E. Carson

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

    David Matuskey, Adam P. Mecca, Brian Pittman, Rajiv Radhakrishnan, Patrick D. Skosnik, Deepak Cyril D’Souza, Irina Esterlis & Christopher H. van Dyck

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

    David Matuskey & Christopher H. van Dyck

  4. Alzheimer’s Disease Research Unit, Yale University School of Medicine, New Haven, CT, USA

    Adam P. Mecca & Christopher H. van Dyck

  5. Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA

    Amy Arnsten & Christopher H. van Dyck

  6. Department of Psychology, Yale University School of Medicine, New Haven, CT, USA

    Amy Arnsten

  7. Bouvé College of Health Sciences, Northeastern University Schools of Nursing & Pharmacy/Pharmaceutical Sciences, Boston, MA, USA

    Patrick D. Skosnik

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Corresponding author

Correspondence to Takuya Toyonaga.

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Toyonaga, T., Khattar, N., Wu, Y. et al. The regional pattern of age-related synaptic loss in the human brain differs from gray matter volume loss: in vivo PET measurement with [11C]UCB-J. Eur J Nucl Med Mol Imaging 51, 1012–1022 (2024). https://doi.org/10.1007/s00259-023-06487-8

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