Blood-brain barrier opening in Alzheimer's disease using MR-guided focused ultrasound methods
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Introduction
Given the compelling preclinical evidence, we investigate for the first time the use of non-invasive MRgFUS to open the BBB in human patients, with mild-to-moderate, amyloid-positive AD. Our primary aim is to evaluate the clinical safety and technical feasibility of this procedure, and secondarily to measure the influence, if any, on clinical and beta-amyloid imaging markers of AD. We find that the BBB can be safely, temporarily, and repeatedly opened in an amyloid-rich brain region with a high degree of anatomic specificity.
Secondary outcome
For our secondary outcome, we did not detect a clinically significant change between 3 months and baseline, on tests of patient cognition or daily functioning. Table lists the clinical psychometric data at baseline and follow-up visits. Group PET changes in the regions of interest (ROIs) after stages 1 and 2 compared to baseline were -0.14 ± 0.22 (standard deviation, n = 5) and -0.08 ± 0.21 ( n = 4), respectively, which were not statistically significant ( p > 0.2, paired t -test, Fig., Supplementary Fig. -, Supplementary Tables, ). Fig. 3 [ 18 F]-Florbetaben uptake on PET before and after treatment. Standardized uptake value ratio images (SUVr) in the corresponding axial planes for [ 18 F]-Florbetaben PET scans at a baseline and b approximately 1 week after sonication...
Discussion
Efficient MRgFUS-mediated BBB opening is influenced by a number of procedural and technical variables. Determining the optimal power via a ramp test is the first step to achieving uniform BBB opening. Other factors include microbubble size and dose, volume and type of tissue targeted, microbubble handling, and coordination between sonication and microbubble injection. As with any procedure, additional experience will enhance its efficiency and success, and while we achieved successful BBB opening in all patients, results were most uniform in the last two patients (Supplementary Fig. ).
MRgFUS procedure
A 3-Tesla MRI (Signa MR750; GE Healthcare, Milwaukee, Wis.) was used to obtain T1, T2 (fast spin echo), and T2* (gradient echo) weighted images for surgical planning. A region in the right frontal lobe was then selected for BBB opening. To minimize the risk, we avoided areas containing sulci and vessels within two contiguous MRI slices in each of the axial, sagittal, and coronal planes. Once the target region was identified, patients received a weight-based intravenous injection of microbubble contrast (Definity®) (4 µl/kg), followed shortly by the application of low-frequency focused ultrasound to the target. MR thermometry was used to monitor tissue temperature at the sonicated region in real time. The sonication parameters were limited by the clinical device hardware and software, and corresponded to those previously tested in large animal models.
Outcomes
The primary outcomes were clinical and radiographic safety as well as technical feasibility of reversible and repeated BBB opening. Successful barrier opening and restoration was determined, respectively, by gadolinium leakage immediately after sonication and by the absence of enhancement 1 day after sonication at the target region on T1-weighted contrast images. Safety was measured by clinical exam during the procedure and at each follow-up, as well as radiographic examination for any adverse events, including hemorrhage, swelling, or mass effect. Follow-up visits were scheduled for 1 day, 1 week, and 1 month after each procedure, as well as 2 months following the second procedure (Fig. ). Adverse events were recorded and monitored in a prospective fashion.
[ 18 F]-Florbetaben PET CT image acquisition and analysis
PET CT scans to measure beta-amyloid deposition were performed at baseline and 1 week following each procedure. A transmission scan followed by a 20-min emission scan (four frame/5 min each) were acquired on the Phillips Gemini PET CT (3D mode) starting at 90 min after an 8 mCi ± 20% ( n = 14) radiotracer injection of [ 18 F]-florbetaben. The SUVr was calculated on a voxel-wise basis by dividing the summed PET images by the cerebellar gray matter ROI, consistent with other [ 18 F]-florbetaben studies. To derive the cerebellar gray matter ROI, the T1-weighted MR images were processed with the Freesurfer pipeline (version 5.1; http://surfer.nmr.mgh.harvard.edu/ ). The radioactivity in the cerebellar reference region was extracted after mapping the cerebellar gray matter ROI to the co-registered [ 18 F]-florbetaben scans. Image preprocessi...
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Evidence quotes (6)
Given the compelling preclinical evidence, we investigate for the first time the use of non-invasive MRgFUS to open the BBB in human patients, with mild-to-moderate, amyloid-positive AD. Our primary aim is to evaluate the clinical safety and technical feasibility of this procedure, and secondarily to measure the influence, if any, on clinical and beta-amyloid imaging markers of AD. We find that the BBB can be safely, temporarily, and repeatedly opened in an amyloid-rich brain region with a high degree of anatomic specificity.
For our secondary outcome, we did not detect a clinically significant change between 3 months and baseline, on tests of patient cognition or daily functioning. Table lists the clinical psychometric data at baseline and follow-up visits. Group PET changes in the regions of interest (ROIs) after stages 1 and 2 compared to baseline were -0.14 ± 0.22 (standard deviation, n = 5) and -0.08 ± 0.21 ( n = 4), respectively, which were not statistically significant ( p > 0.2, paired t -test, Fig., Supplementary Fig. -, Supplementary Tables, ). Fig. 3 [ 18 F]-Florbetaben uptake on PET before and after treatment. Standardized uptake value ratio images (SUVr) in the corresponding axial planes for [ 18 F]-Florbetaben PET scans at a baseline and b approximately 1 week after sonication. c Gadolinium extravasation on T1-weighted MR images immediately after the blood-brain barrier disruption procedure demonstrates the targeted region
Efficient MRgFUS-mediated BBB opening is influenced by a number of procedural and technical variables. Determining the optimal power via a ramp test is the first step to achieving uniform BBB opening. Other factors include microbubble size and dose, volume and type of tissue targeted, microbubble handling, and coordination between sonication and microbubble injection. As with any procedure, additional experience will enhance its efficiency and success, and while we achieved successful BBB opening in all patients, results were most uniform in the last two patients (Supplementary Fig. ).
A 3-Tesla MRI (Signa MR750; GE Healthcare, Milwaukee, Wis.) was used to obtain T1, T2 (fast spin echo), and T2* (gradient echo) weighted images for surgical planning. A region in the right frontal lobe was then selected for BBB opening. To minimize the risk, we avoided areas containing sulci and vessels within two contiguous MRI slices in each of the axial, sagittal, and coronal planes. Once the target region was identified, patients received a weight-based intravenous injection of microbubble contrast (Definity®) (4 µl/kg), followed shortly by the application of low-frequency focused ultrasound to the target. MR thermometry was used to monitor tissue temperature at the sonicated region in real time. The sonication parameters were limited by the clinical device hardware and software, and corresponded to those previously tested in large animal models.
The primary outcomes were clinical and radiographic safety as well as technical feasibility of reversible and repeated BBB opening. Successful barrier opening and restoration was determined, respectively, by gadolinium leakage immediately after sonication and by the absence of enhancement 1 day after sonication at the target region on T1-weighted contrast images. Safety was measured by clinical exam during the procedure and at each follow-up, as well as radiographic examination for any adverse events, including hemorrhage, swelling, or mass effect. Follow-up visits were scheduled for 1 day, 1 week, and 1 month after each procedure, as well as 2 months following the second procedure (Fig. ). Adverse events were recorded and monitored in a prospective fashion.
PET CT scans to measure beta-amyloid deposition were performed at baseline and 1 week following each procedure. A transmission scan followed by a 20-min emission scan (four frame/5 min each) were acquired on the Phillips Gemini PET CT (3D mode) starting at 90 min after an 8 mCi ± 20% ( n = 14) radiotracer injection of [ 18 F]-florbetaben. The SUVr was calculated on a voxel-wise basis by dividing the summed PET images by the cerebellar gray matter ROI, consistent with other [ 18 F]-florbetaben studies. To derive the cerebellar gray matter ROI, the T1-weighted MR images were processed with the Freesurfer pipeline (version 5.1; http://surfer.nmr.mgh.harvard.edu/ ). The radioactivity in the cerebellar reference region was extracted after mapping the cerebellar gray matter ROI to the co-registered [ 18 F]-florbetaben scans. Image preprocessing was performed with statistical parametric mapping, version eight (SPM8, Institute of Neurology, London). PET-to-PET and MR-to-PET registrations were performed using the normalized mutual information algorithm, and images were spatially normalized into standard 3D space relative to the anterior co...
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