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[64Cu]Cu-Albumin Clearance Imaging to Evaluate Lymphatic Efflux of Cerebrospinal Space Fluid in Mouse Model

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Abstract

Purpose

Clearance of brain waste in the cerebrospinal fluid (CSF) through the meningeal lymphatic vessels (mLV) has been evaluated mostly through the fluorescent imaging which has inherent limitations in the context of animal physiology and clinical translatability. The study aimed to establish molecular imaging for the evaluation of mLV clearance function.

Methods

Radionuclide imaging after intrathecal (IT) injection was acquired in C57BL/6 mice of 2–9 months. The distribution of [99mTc]Tc-diethylenetriamine pentaacetate (DTPA) and [64Cu]Cu-human serum albumin (HSA) was comparatively evaluated. Evans Blue and [64Cu]Cu-HSA were used to evaluate the distribution of tracer under various speed and volume conditions.

Results

[99mTc]Tc-DTPA is not a suitable tracer for evaluation of CSF clearance via mLV as no cervical lymph node uptake was observed while it was cleared from the body. A total volume of 3 to 9 μL at an infusion rate of 300 to 500 nL/min was not sufficient for the tracer to reach the cranial subarachnoid space and clear throughout the mLV. As a result, whole-body positron emission tomography imaging using [64Cu]Cu-HSA at 700 nL/min, to deliver 6 μL of injected volume, was set for characterization of the CSF to mLV clearance. Through this protocol, the mean terminal CSF clearance half-life was measured to be 123.6 min (range 117.0–135.0) in normal mice.

Conclusions

We established molecular imaging to evaluate CSF drainage through mLV using [64Cu]Cu-HSA. This imaging method is expected to be extended in animal models of dysfunctional meningeal lymphatic clearance and translational research for disease-modifying therapeutic approaches.

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Data Availability

The data and material can be made be available upon communication with the corresponding author.

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Acknowledgements

Youngjoo Kim and Shin Jin Seop for their technical assistance.

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Authors and Affiliations

  1. Department of Nuclear Medicine, College of Medicine, Seoul National University, Seoul, Korea

    Azmal Sarker, Hyeyeon Seo, Yun-Sang Lee & Dong Soo Lee

  2. Department of Nuclear Medicine, Seoul National University Hospital, Seoul, 03080, Republic of Korea

    Minseok Suh, Yoori Choi, Ji Yong Park, Yun-Sang Lee & Dong Soo Lee

  3. Biomedical Research Center, Seoul National University Hospital, Seoul, Korea

    Yoori Choi, Seokjun Kwon & Hyun Kim

  4. Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 03080, Republic of Korea

    Yoori Choi, Eunji Lee & Dong Soo Lee

  5. Dental Research Institute, Seoul National University, Seoul, 101, South Korea

    Ji Yong Park

  6. Medical Research Center, College of Medicine, Seoul National University, Seoul, Korea

    Dong Soo Lee

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  1. Azmal Sarker
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The first, second, third, ninth, and last authors were responsible for the study design. The first and second authors were responsible for interpretation of data and manuscript drafting. The first eight authors were also responsible for performing experiments and data documentation.

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Correspondence to Minseok Suh or Dong Soo Lee.

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Competing Interests

Azmal Sarker was supported by SNU Presidential Fellowship. Minseok Suh, Yoori Choi, Ji Yong Park, Hyeyeon Seo, Seokjun Kwon, Hyun Kim, Eunji Lee, and Dong Soo Lee declares that they have no conflict of interest.

Ethics Approval and Consent to Participate

The study and experiment methodology of this study were approved by the Institutional Review Board and Institutional Animal Care and Use Committee (registration number SNU-200513-8) of Seoul National University College of Medicine. All experiments were conducted under relevant guidelines and regulations regarding the care and the use of animals for the experimental procedures.

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This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIP) (No. 2020R1A2C2101069 and No. 2021R1F1A1064340).

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Sarker, A., Suh, M., Choi, Y. et al. [64Cu]Cu-Albumin Clearance Imaging to Evaluate Lymphatic Efflux of Cerebrospinal Space Fluid in Mouse Model. Nucl Med Mol Imaging 56, 137–146 (2022). https://doi.org/10.1007/s13139-022-00746-6

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