Non-invasive MRI Study of Blood-Cerebrospinal Fluid Barrier Function in a Mouse Model of Alzheimer’s Disease

Academic Background

Alzheimer’s Disease (AD) is a common neurodegenerative disorder characterized by the accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles. Recent studies have increasingly shown that the Blood-Cerebrospinal Fluid Barrier (BCSFB) plays a significant role in the pathological process of AD. The BCSFB, primarily composed of the Choroid Plexus (CP), is responsible for the production and clearance of Cerebrospinal Fluid (CSF). Dysfunction of the BCSFB may lead to the accumulation of toxic proteins, thereby accelerating the progression of AD. However, due to the lack of non-invasive detection methods, the dynamic changes of the BCSFB in AD have not been fully studied.

To address this issue, researchers developed a new method using Arterial Spin Labeling Magnetic Resonance Imaging (ASL MRI) to measure BCSFB function and validated it in a mouse model of AD. This study aims to reveal changes in BCSFB function during the early stages of AD and explore its potential as a biomarker for AD pathology.

Source of the Paper

This paper was co-authored by Charith Perera, Renata Cruz, and other researchers from institutions such as University College London (UCL) in the UK and the Champalimaud Research Centre in Portugal. The study was published in 2024 in the journal Fluids and Barriers of the CNS, titled Non-invasive MRI of blood-cerebrospinal fluid-barrier function in a mouse model of Alzheimer’s disease: a potential biomarker of early pathology.

Research Process

1. Experimental Animals and Grouping

The study used the triple-transgenic AD mouse model (3xTg-AD), which mimics the amyloid plaque and neurofibrillary tangle pathology of AD. The control group consisted of B6129SF2/J mice. The experiment was divided into four time points: 8 weeks (preclinical stage), 14 weeks, 20 weeks, and 32 weeks, corresponding to different stages of AD development. Each group included 10 3xTg mice and 7-10 control mice.

2. Behavioral Testing

To assess cognitive function, researchers conducted the Y-maze Spontaneous Alternation Test. This test evaluates short-term memory and exploratory behavior by recording the mice’s exploration patterns in the maze. The results showed significant behavioral differences in 3xTg mice at 20 and 32 weeks, particularly a reduction in the number of maze explorations.

3. MRI Data Acquisition

Researchers used a 9.4T Bruker Biospec MRI scanner combined with a cryogenic receive coil to perform ASL MRI scans on the mice. ASL MRI quantifies tissue perfusion and BCSFB function by labeling arterial blood water and measuring the time difference of its inflow into tissues. The specific steps were as follows:

• Standard ASL Scan: Used to measure Cerebral Blood Flow (CBF) in the cortex, hippocampus, and midbrain.
• BCSFB-ASL Scan: Utilized an ultra-long echo time (TE) to detect the process of labeled blood water crossing the BCSFB into the CSF, thereby quantifying BCSFB-mediated water delivery.

4. Data Analysis

Researchers calculated CBF and BCSFB-mediated water delivery rates by fitting the Buxton kinetic model. Additionally, they measured the T1 value of CSF (T1CSF) and lateral ventricular volume. The results showed that BCSFB-mediated water delivery was significantly higher in 3xTg mice at all time points compared to controls, while CBF and T1 values showed no significant differences between the groups.

5. Histological Validation

To validate AD pathology, researchers performed immunohistochemical staining on mouse brain tissue to detect Aβ and tau protein deposition. The results showed that Aβ plaques began to appear in 3xTg mice at 14 weeks, and neurofibrillary tangles appeared at 20 weeks, while no significant pathological changes were observed in control mice.

Key Findings

1. Enhanced BCSFB Function: BCSFB-mediated water delivery was significantly higher in 3xTg mice at all time points, indicating changes in BCSFB function during the early stages of AD.
2. No Significant Difference in Cerebral Blood Flow: Although CBF was slightly higher in 3xTg mice compared to controls, the difference was not statistically significant.
3. Behavioral Changes: 3xTg mice showed reduced exploratory behavior at 20 and 32 weeks, suggesting cognitive decline.
4. Histological Validation: Immunohistochemical staining confirmed the deposition of Aβ plaques and tau protein in the brains of 3xTg mice, further supporting the presence of AD pathology.

Conclusion

This study demonstrates that significant changes in BCSFB function occur during the early stages of AD, preceding behavioral changes and widespread neurofibrillary tangle deposition. By using non-invasive ASL MRI technology, researchers successfully quantified BCSFB function and proposed its potential as an early biomarker for AD pathology. This finding provides new insights for the early diagnosis and treatment of AD.

Research Highlights

1. Non-invasive Detection: The study is the first to use ASL MRI technology to non-invasively measure BCSFB function in an AD mouse model.
2. Early Pathological Biomarker: Changes in BCSFB function occur earlier than behavioral changes, suggesting its potential as an early diagnostic marker for AD.
3. Multimodal Validation: The study combined MRI, behavioral testing, and histological analysis to comprehensively validate the dynamic changes in AD pathology.

Research Value

This study not only reveals changes in BCSFB function during the early stages of AD but also provides a theoretical foundation for developing new diagnostic tools for AD. By applying this non-invasive MRI technology, it may be possible to achieve early diagnosis and intervention for AD in clinical settings in the future. Additionally, the study opens new research directions for further exploring the role of the BCSFB in AD pathology.