Non-Invasive Imaging Technique for Evaluating Trans-Barrier Water Exchange in the Choroid Plexus

Background Introduction

The choroid plexus (CP) is a critical site for cerebrospinal fluid (CSF) production and an essential component of the blood-cerebrospinal fluid barrier (BCSFB). The CP regulates CSF secretion and absorption, maintaining brain homeostasis. However, the lack of non-invasive imaging techniques to assess CP function has hindered a deeper understanding of BCSFB functionality. Current methods, such as tracer dilution and CSF collection, can indirectly measure CSF secretion but are invasive and cannot accurately distinguish the contribution of the CP from other potential sources (e.g., the blood-brain barrier).

In recent years, researchers have proposed measuring the water efflux rate from the CP to CSF (kbc) as a biomarker for evaluating BCSFB integrity. This metric has shown significant declines in aged mice and patients with mild cognitive impairment, suggesting its potential as an important biomarker for CP function. However, existing magnetic resonance imaging (MRI) techniques in this field remain limited, often relying on contrast agents. Therefore, developing a contrast-agent-free MRI technique to measure kbc holds significant scientific and clinical value.

Research Source

This study was co-authored by Xuetao Wu, Qingping He, Yu Yin, Shuyuan Tan, Baogui Zhang, Weiyun Li, Yi-Cheng Hsu, Rong Xue, and Ruiliang Bai, affiliated with institutions such as the Institute of Biophysics at the Chinese Academy of Sciences and Zhejiang University. The research was published in 2024 in the journal Fluids and Barriers of the CNS, titled “Relaxation-Exchange Magnetic Resonance Imaging (REXI): A Non-Invasive Imaging Method for Evaluating Trans-Barrier Water Exchange in the Choroid Plexus.”

Research Process and Experimental Design

1. Development and Validation of REXI Technology

REXI (Relaxation-Exchange Magnetic Resonance Imaging) is a novel, contrast-agent-free MRI technique designed to assess BCSFB function by measuring the water exchange rate between the CP and CSF. REXI leverages the significant difference in transverse relaxation times (T2) between CP tissue (e.g., blood vessels and epithelial cells) and CSF, comprising three main modules: a filter block, a mixing block, and a detection block.

• Filter Block: An optimized echo time (Tef) is used to suppress most of the magnetization signal from CP tissue (shorter T2) while minimizing the impact on CSF signal (longer T2).
• Mixing Block: After filtering, the remaining magnetization is stored back in the longitudinal direction, allowing water exchange between the CP and CSF over varying mixing times ™.
• Detection Block: Multi-echo acquisition is used to quantify the component fractions of the CP and CSF after exchange.

To validate REXI’s feasibility, preliminary tests were conducted on urea-water phantoms, a well-established two-site exchange system where proton exchange rates can be manipulated by adjusting pH. Twelve urea-water phantoms with different pH levels (6.7 and 7.0) were prepared and tested using a 9.4 T preclinical MRI scanner.

2. Animal Experiments

Following the validation of REXI, experiments were conducted on a rat model. The subjects were eight 11-12-week-old Wistar Kyoto (WKY) rats. The experiments were divided into two parts: a scan-rescan experiment and a drug-induced CP dysfunction experiment.

• Scan-Rescan Experiment: Aimed to validate the reproducibility of REXI in measuring kbc. Each rat underwent two scans within the same session, and the reproducibility of kbc, fshort (magnetization fraction of the short-T2 component), and T2 values was calculated.
• Drug-Induced Experiment: Intravenous injection of the carbonic anhydrase inhibitor acetazolamide was used to induce CP dysfunction. Acetazolamide significantly reduces CSF secretion, thereby testing REXI’s sensitivity in detecting CP dysfunction.

Key Findings

1. Urea-Water Phantom Results

In the urea-water phantoms, REXI successfully captured changes in proton exchange rates at different pH levels. As pH decreased, the proton exchange rate significantly increased, consistent with the acid-catalyzed proton exchange mechanism in urea solutions. Additionally, REXI detected a reduction in T2 values for both urea and water protons as pH decreased, further validating its sensitivity to exchange processes.

2. Rat Model Results

In the rat CP, REXI significantly suppressed the CP tissue signal, reducing fshort from 0.44 to 0.23. As the mixing time increased, fshort gradually recovered to 0.28, indicating water exchange between the CP and CSF. Using a two-site exchange model (2SXM), the researchers calculated a steady-state water efflux rate (kbc) of 0.49 s⁻¹. The scan-rescan experiment demonstrated high reproducibility in measuring kbc (intraclass correlation coefficient ICC = 0.90).

In the drug-induced experiment, acetazolamide significantly reduced kbc by 66%, further proving REXI’s sensitivity in detecting CP dysfunction.

Conclusions and Significance

This study introduces and validates REXI, a non-invasive technique for measuring the water exchange rate between the CP and CSF, providing a new biomarker for assessing BCSFB function. The development of REXI not only fills a gap in existing techniques but also offers a valuable tool for future research on the role of the CP in neurodegenerative diseases such as Alzheimer’s. Moreover, REXI’s high reproducibility and sensitivity make it a promising candidate for clinical applications, particularly in evaluating CSF secretion abnormalities and related brain disorders.

Research Highlights

1. Innovation: REXI is a novel, contrast-agent-free MRI technique that enables non-invasive measurement of water exchange between the CP and CSF for the first time.
2. High Reproducibility: The scan-rescan experiment demonstrated high reproducibility in measuring kbc, with an ICC of 0.90.
3. Sensitivity: REXI sensitively detected acetazolamide-induced CP dysfunction, with a 66% reduction in kbc.
4. Application Potential: REXI provides a valuable tool for future research on the CP’s role in brain disorders and has broad clinical application prospects.

Additional Valuable Information

The success of this study lies not only in the development of REXI but also in the validation process using urea-water phantoms and rat models. These models provide important references for future similar studies. Additionally, the development of REXI offers new insights for other relaxation-exchange-based MRI techniques (e.g., REXSY), particularly in reducing scan time and improving spatial resolution.

The introduction of REXI opens new avenues for CSF dynamics research and is expected to play a significant role in neuroscience and clinical medicine in the future.