Focused ultrasound–mediated blood-brain barrier opening in Alzheimer’s disease: long-term safety, imaging, and cognitive outcomes

Abstract

OBJECTIVE MRI-guided low-intensity focused ultrasound (FUS) has been shown to reversibly open the blood-brain barrier (BBB), with the potential to deliver therapeutic agents noninvasively to target brain regions in patients with Alzheimer’s disease (AD) and other neurodegenerative conditions. Previously, the authors reported the short-term safety and feasibility of FUS BBB opening of the hippocampus and entorhinal cortex (EC) in patients with AD. Given the need to treat larger brain regions beyond the hippocampus and EC, brain volumes and locations treated with FUS have now expanded. To evaluate any potential adverse consequences of BBB opening on disease progression, the authors report safety, imaging, and clinical outcomes among participants with mild AD at 6–12 months after FUS treatment targeted to the hippocampus, frontal lobe, and parietal lobe. METHODS In this open-label trial, participants with mild AD underwent MRI-guided FUS sonication to open the BBB in β-amyloid positive regions of the hippocampus, EC, frontal lobe, and parietal lobe. Participants underwent 3 separate FUS treatment sessions performed 2 weeks apart. Outcome assessments included safety, imaging, neurological, cognitive, and florbetaben β-amyloid PET. RESULTS Ten participants (range 55–76 years old) completed 30 separate FUS treatments at 2 participating institutions, with 6–12 months of follow-up. All participants had immediate BBB opening after FUS and BBB closure within 24–48 hours. All FUS treatments were well tolerated, with no serious adverse events related to the procedure. All 10 participants had a minimum of 6 months of follow-up, and 7 participants had a follow-up out to 1 year. Changes in the Alzheimer’s Disease Assessment Scale–cognitive and Mini-Mental State Examination scores were comparable to those in controls from the Alzheimer’s Disease Neuroimaging Initiative. PET scans demonstrated an average β-amyloid plaque of 14% in the Centiloid scale in the FUS-treated regions. CONCLUSIONS This study is the largest cohort of participants with mild AD who received FUS treatment, and has the longest follow-up to date. Safety was demonstrated in conjunction with reversible and repeated BBB opening in multiple cortical and deep brain locations, with a concomitant reduction of β-amyloid. There was no apparent cognitive worsening beyond expectations up to 1 year after FUS treatment, suggesting that the BBB opening treatment in multiple brain regions did not adversely influence AD progression. Further studies are needed to determine the clinical significance of these findings. FUS offers a unique opportunity to decrease amyloid plaque burden as well as the potential to deliver targeted therapeutics to multiple brain regions in patients with neurodegenerative disorders.

A patient-derived amyotrophic lateral sclerosis blood-brain barrier cell model reveals focused ultrasound-mediated anti-TDP-43 antibody delivery

“…With BBB limiting an estimated 99.8 % of peripherally administered large molecule drugs such as therapeutics antibodies (95), we next tested the possibility of enhancing the permeabilisation of ALS BBB to large molecules with FUS +MB . As a proof-of-concept, we trialled the delivery of anti-TDP-43 antibody, considering promising preclinical development of TDP-43 targeted immunotherapies (96)(97)(98)(99) as well as the recent clinical success of therapeutic antibodies in the treatment of other neurodegenerative disorders (100)(101)(102)(103)(104). Although the utilised anti-TDP-43 antibody has not yet proved therapeutically beneficial, we were previously successful in delivering Aducanumab (Aduhelm TM ) and anti-tau therapeutic antibodies with FUS +MB in human Alzheimer's disease in vitro models (37,41); and a recent clinical study demonstrated beneficial effects of Aducanumab combined with FUS +MB in Alzheimer's disease patients, as compared to Aducanumab alone (104).…”

“…As a proof-of-concept, we trialled the delivery of anti-TDP-43 antibody, considering promising preclinical development of TDP-43 targeted immunotherapies (96)(97)(98)(99) as well as the recent clinical success of therapeutic antibodies in the treatment of other neurodegenerative disorders (100)(101)(102)(103)(104). Although the utilised anti-TDP-43 antibody has not yet proved therapeutically beneficial, we were previously successful in delivering Aducanumab (Aduhelm TM ) and anti-tau therapeutic antibodies with FUS +MB in human Alzheimer's disease in vitro models (37,41); and a recent clinical study demonstrated beneficial effects of Aducanumab combined with FUS +MB in Alzheimer's disease patients, as compared to Aducanumab alone (104). Hence, we hypothesised that analogously, achieving increased permeability of this model anti-TDP-43 antibody in our cell platform could be representative of future clinically approved ALS immunotherapeutics.…”

Strategies to target the central nervous system HIV reservoir

“…While it has been suggested that, in some instances, the BBB integrity could already be compromised by the occurring disease [48], thus facilitating the trafficking of antibodies to the brain, the improvement of antibody delivery in the CNS is an area of active research. Recently, Alzheimer's disease researchers used focused ultrasound to disrupt specific sections of the BBB, leading to an improved penetration of antibeta-amyloid antibodies into the brain, focally enhancing the removal of amyloid plaques [49 ▪ ]. Increased transport through the BBB could also be achieved by creating antibodies with improved binding to Fc Receptor [50 ▪ ] or with bifunctional properties [51].…”

Transcranial Blood–Brain Barrier Opening in Alzheimer’s Disease Patients Using a Portable Focused Ultrasound System with Real-Time 2-D Cavitation Mapping

“…The primary objective of the study is to assess the safety and feasibility of FUS-induced BBBO in Alzheimer's disease patients, using a portable, noninvasive FUS system. Secondary objectives includes testing the feasibility of cavitation mapping and observing changes in 18 F-Florbetapir PET and in blood biomarkers. Six Alzheimer's disease patients (2M/4F, age = 69.7±7.2 yr) were enrolled in a phase 1 trial under FDA and Columbia University IRB approval (NCT04118764) (Table 1).…”

“…Figure 7 shows the percent changes in standard uptake value ratio (SUVR) or asymmetry SUVR of 18 F-Florbetapir compared to the baseline. Subject 3 was excluded due to the absence of BBBO.…”