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Multimodal MR Imaging Reveals the Mechanisms of Post-Cardiac-Arrest Brain edema: Ferroptosis-Mediated BBB Disruption
Yunke Tan1, HaoYi Ye2, Qiulin Ge1
1Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Background:
The role of ferroptosis in Cardiac arrest (CA)-induced cerebral edema remains unclear.
Purpose:
To investigate whether ferroptosis contributes to blood-brain barrier (BBB) disruption and aquaporin-4 (AQP4) dysfunction following CA.
Study Type:
Prospective.
Animal Model:
Asphyxia-induced CA rat model. Forty two rats were used and assigned to the CA (24) and the sham (18) group.
Field Strength/Sequence:
T2-weighted anatomical imaging with 2D turbo spin-echo sequence, QSM with 3D GRE sequence, IVIM with 2D RESOLVE EPI sequence, 1H-MRS with SVS-PRESS sequence.
Assessment:
Multiparametric MRI was performed 24 h after return of spontaneous circulation (ROSC). Imaging findings were validated using histology, immunohistochemistry, Western blot, and transmission electron microscopy.
Statistical Tests:
Unpaired two-tailed Student's T-test was used. A p value less than 0.05 was considered statistically significant.
Results:
CA led to marked neurological deficits, although no obvious abnormalities were observed on T 2-weighted MRI. QSM revealed marked iron accumulation in the hippocampus, which was associated with elevated ROS, lipid peroxidation, and altered expression of ferroptosis-related markers (downregulation of GPX4 and upregulation of ACSL4). Electron microscopy confirmed mitochondrial changes characteristic of ferroptosis. Ferroptosis-induced lipid peroxidation resulted in degradation of tight-junction proteins (ZO-1 and occludin), BBB leakage (elevated serum S100β), and loss of AQP4 polarity. IVIM showed a selective reduction in true tissue diffusivity (IVIM D), indicating cytotoxic edema. 1H-MRS revealed decreased N-acetylaspartate, increased lipid peaks, and reduced myo-inositol levels, consistent with neuronal death and astrocytic swelling.
Data Conclusion:
This study provides evidence for a sequential cascade after CA and ROSC in which iron overload is associated with ferroptosis, which is linked to disruption of the blood-brain barrier. This barrier disruption coincides with AQP4 depolarization, inducing cytotoxic and vasogenic edema, which, along with depolarization, is accompanied by neuronal death. Multimodal MRI noninvasively captures this process, offering an early detection and monitoring platform for ferroptosis-related brain injury and underscoring its potential as a translational tool for neuroprotective interventions.
Evidence Level:
1.
Technical Efficacy:
Stage 1.
Insights
Cardiac arrest (CA) triggers iron overload and ferroptosis, leading to blood-brain barrier (BBB) disruption and brain edema. Multimodal MRI noninvasively detects this ferroptosis-related brain injury after CA and return of spontaneous circulation (ROSC).
Area of Science:
- Neuroscience
- Biochemistry
- Radiology
Background:
- The precise role of ferroptosis in cerebral edema following cardiac arrest (CA) is not well understood.
- Investigating ferroptosis is crucial for understanding brain injury mechanisms after CA.
Purpose of the Study:
- To determine if ferroptosis contributes to blood-brain barrier (BBB) disruption after CA.
- To assess the impact of ferroptosis on aquaporin-4 (AQP4) function post-CA.
- To explore the potential of multiparametric MRI in detecting ferroptosis-related brain injury.
Main Methods:
- A prospective study using an asphyxia-induced CA rat model.
- Multiparametric MRI (T2-weighted, QSM, IVIM, 1H-MRS) was performed 24 hours post-ROSC.
- Histology, immunohistochemistry, Western blot, and electron microscopy validated MRI findings.
Main Results:
- CA induced neurological deficits and hippocampal iron accumulation, confirmed by QSM.
- Elevated oxidative stress and ferroptosis markers (GPX4, ACSL4) were observed.
- Ferroptosis led to BBB leakage, AQP4 depolarization, cytotoxic edema (IVIM D reduction), and neuronal damage (1H-MRS findings).
Conclusions:
- A sequential cascade of iron overload, ferroptosis, BBB disruption, and edema occurs after CA and ROSC.
- Multimodal MRI can noninvasively detect and monitor ferroptosis-related brain injury.
- This approach offers a potential platform for evaluating neuroprotective interventions.
