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Dataset Description
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Cerebral cavernous malformations (CCMs) are vascular lesions within the central nervous system that can cause debilitating neurological symptoms. Currently, surgical excision and stereotactic radiosurgery, the primary treatment options, can pose significant risks to some patients. Here, we tested whether a pulsed, low intensity, focused ultrasound-microbubble (FUS-MB) treatment that transiently opens the blood-brain barrier and has shown therapeutic potential in mouse models of Alzheimer’s disease could control CCM growth and formation in a clinically-representative (Krit1 null) murine model. FUS-MB under MRI-guidance consistently opened the blood-brain barrier, with gadolinium contrast agent deposition most evident at perilesional boundaries. Remarkably, longitudinal MRI revealed that, at 1 month after treatment, FUS-MB had completely halted the growth of virtually all (94%) treated CCMs. In contrast, untreated CCMs grew ~7-fold in volume during this same period. At the cellular level, FUS-MB-treated CCMs exhibited a marked reduction in Krit1 null endothelial cells. Moreover, in mice receiving multiple FUS-MB treatments with fixed peak-negative pressures, de novo CCM formation was reduced by 81%, indicating a prophylactic effect of FUS-MB for CCM. Simulated treatment plans on MRIs of CCM patients who had been treated with stereotactic radiosurgery revealed that their lesions are amenable to FUS-MB treatment with current clinical technology. Our findings support FUS-MB as a minimally-invasive treatment modality that can safely arrest murine CCM growth and prevent de novo CCM formation in mice. If proven safe and effective in clinical trials, FUS-MB treatment offers the potential to enhance therapeutic options for CCM patients. MR imaging was performed using either a 7T Bruker/Siemens ClinScan or a 9.4T Bruker BioSpec small animal MRI scanner. T2-weighted spin echo images were acquired at 7T with the Siemens 3D T2-SPACE sequence (repetition time of 3000 ms, echo time of 80 ms, voxel size of 125 μm x 125 μm x 100 μm, 2 averages, and 20 min acquisition time) or at 9.4T with the Bruker 3D T2-TurboRARE sequence (repetition time of 2000 ms, echo time of 55 ms, turbo factor of 18, voxel size of 125 μm x 125 μm x 125 μm, 1 average, and 30 min acquisition time). Susceptibility-weighted images were acquired only at 7T (repetition time of 18 ms, echo time of 10 ms, voxel size of 130 μm x 130 μm x 130 μm, 2 averages, and 15 min acquisition time). T1-weighted spin echo images were acquired at 9.4T with the Bruker 2D T1-RARE sequence (repetition time of 1500 ms, echo time of 6 ms, voxel size of 156 μm x 156 μm x 350 μm, 1 average, and 3 min acquisition time). All imaging was performed under isoflurane anesthesia, and body temperature was maintained with a heated, circulating water bed.
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