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

Azmal Sarker; Minseok Suh; Yoori Choi; Ji Yong Park; Seokjun Kwon; Hyun Kim; Eunji Lee; Hyeyeon Seo; Yun-Sang Lee; Dong Soo Lee

doi:10.1007/s13139-022-00746-6

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

Nucl Med Mol Imaging. 2022 Jun;56(3):137-146. doi: 10.1007/s13139-022-00746-6. Epub 2022 Apr 2.

Authors

Azmal Sarker¹, Minseok Suh², Yoori Choi^{2

3

4}, Ji Yong Park^{2

5}, Seokjun Kwon³, Hyun Kim³, Eunji Lee⁴, Hyeyeon Seo¹, Yun-Sang Lee^{1

2}, Dong Soo Lee^{1

2

4

6}

Affiliations

¹ Department of Nuclear Medicine, College of Medicine, Seoul National University, Seoul, Korea.
² Department of Nuclear Medicine, Seoul National University Hospital, Seoul, 03080 Republic of Korea.
³ Biomedical Research Center, Seoul National University Hospital, Seoul, Korea.
⁴ Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 03080 Republic of Korea.
⁵ Dental Research Institute, Seoul National University, Seoul, 101 South Korea.
⁶ Medical Research Center, College of Medicine, Seoul National University, Seoul, Korea.

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.

Supplementary information: The online version contains supplementary material available at 10.1007/s13139-022-00746-6.

Keywords: Cerebrospinal fluid; Meningeal lymphatics; Molecular imaging.