Summary

Antiamyloid antibodies have been used to reduce cerebral amyloid-beta (Aβ) load in patients with Alzheimer’s disease. We applied focused ultrasound with each of six monthly aducanumab infusions to temporarily open the blood–brain barrier with the goal of enhancing amyloid removal in selected brain regions in three participants over a period of 6 months. The reduction in the level of Aβ was numerically greater in regions treated with focused ultrasound than in the homologous regions in the contralateral hemisphere that were not treated with focused ultrasound, as measured by fluorine-18 florbetaben positron-emission tomography. Cognitive tests and safety evaluations were conducted over a period of 30 to 180 days after treatment. 

Discussion

Several studies have shown that focused ultrasound can safely and transiently open the blood–brain barrier in patients with Alzheimer’s disease and other neurologic disorders.^3-13 The effect of using focused ultrasound to open the blood–brain barrier alone, without application of antiamyloid treatment, on levels of Aβ in patients with Alzheimer’s disease has been reported.^5,6,12,13,25 The results of these studies have varied with regard to the number of focused ultrasound treatments, treatment volumes, timelines, and brain regions treated. Reported reductions in the levels of Aβ with the use of focused ultrasound to open the blood–brain barrier alone have been nearly imperceptible in some studies; in studies with 5 to 10 patients, reductions in the levels of Aβ (measured as SUVRs) have been 1.6 to 6.6% over periods of 9 to 16 weeks.^{3,5,6,12,13,25} Comparisons of our trial results with those from previous studies are limited, given the differences in designs. However, we found that the combination of focused ultrasound to open the blood–brain barrier and administration of aducanumab resulted in numerically greater reductions in Aβ levels, as measured as both SUVR and centiloid values, than previously observed in studies that assessed the use of focused ultrasound alone. We observed an average 32% reduction in SUVR (for the three participants combined) after 26 weeks in the regions that had received treatment to open the blood–brain barrier and six combination treatments. There was also a greater reduction in Aβ levels in the regions of the brain that had received treatment to open the blood–brain barrier than in the homologous regions in the contralateral hemisphere that were not treated with focused ultrasound. These results are consistent with those of experimental studies that have shown increased penetration of aducanumab when combined with focused ultrasound to open the blood–brain barrier.^16,17 However, our trial did not quantify monoclonal antibody penetration, and therefore enhanced delivery of the monoclonal antibody was not directly shown.

In our trial design, focused ultrasound was applied to one hemisphere only, allowing comparison between homologous brain regions in each participant. This design controls for several variables, such as antibody infusion, disease progression, and brain targets, and provides an appropriate comparator between homologous brain regions. In the three participants, brain regions with high levels of Aβ were treated with the use of focused ultrasound, and the Aβ results were averaged for comparison with those in homologous regions on the contralateral hemisphere of the brain.

Participants’ clinical and cognitive aspects were assessed mainly for safety, because the trial was not powered to detect clinical changes. No serious adverse neurologic, cognitive, behavioral, or imaging–related adverse events were observed during the 6-month combination-treatment phase. We did not observe any amyloid-related imaging abnormalities; however, persons at highest risk for amyloid-related imaging abnormalities (APOE-ε4 heterozygotes or homozygotes) were excluded as a risk-mitigation strategy. Although the cognitive worsening observed in Participant 3 at 30 days in the follow-up phase is of concern, there was no change in that participant’s neurologic status or activities of daily life. Given the small number of participants, it is difficult to determine whether the cognitive changes were related to disease or a procedure. The neurologic scores of Participants 1 and 2 have remained essentially stable (at 180 and 90 days, respectively) in the follow-up phase.

In this proof-of-concept trial involving three participants, combining aducanumab infusion therapy with regional focused ultrasound to open the blood–brain barrier in participants with mild Alzheimer’s disease was associated with few adverse events (mainly headache), and, during the 6-month combination-treatment phase, resulted in a greater reduction in the level of Aβ than aducanumab therapy alone in homologous regions that were not treated with the use of focused ultrasound.