Blood-brain barrier opening in Alzheimer's disease using MR-guided focused ultrasound.

Magnetic resonance-guided focused ultrasound in combination with intravenously injected microbubbles has been shown to transiently open the blood-brain barrier, and reduce beta-amyloid and tau pathology in animal models of Alzheimer's disease. Here, we used focused ultrasound to open the blood-brain barrier in five patients with early to moderate Alzheimer's disease in a phase I safety trial. In all patients, the blood-brain barrier within the target volume was safely, reversibly, and repeatedly opened. Opening the blood-brain barrier did not result in serious clinical or radiographic adverse events, as well as no clinically significant worsening on cognitive scores at three months compared to baseline. Beta-amyloid levels were measured before treatment using [<sup>18</sup>F]-florbetaben PET to confirm amyloid deposition at the target site. Exploratory analysis suggested no group-wise changes in amyloid post-sonication. The results of this safety and feasibility study support the continued investigation of focused ultrasound as a potential novel treatment and delivery strategy for patients with Alzheimer's disease.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To evaluate the clinical safety and technical feasibility of non-invasive MR-guided focused ultrasound with intravenously injected microbubbles to transiently open the blood–brain barrier in patients with mild-to-moderate, amyloid-positive Alzheimer’s disease.

Animal model / Human subject Homo sapiens (human Alzheimer’s disease patients); strain: N/A; age: 50–85 years (five patients enrolled); sex: male and female

Disease model Alzheimer's disease

MRI or image guidance method MRI-guided (MRgFUS) using a Cosman-Roberts-Wells (CRW) stereotactic frame coupled to the helmet transducer, intraoperative 3T MRI (T1/T2/T2*) for planning, MR thermometry for real-time monitoring, real-time acoustic/hydrophone feedback (cavitation detection), and gadolinium-enhanced T1 verification of BBB opening.

Targeted brain region(s) Superior Frontal Gyrus White Matter Of The Dorsolateral Prefrontal Cortex (Dlpfc)

Route of administration intravenous

Outcomes and Safety

Summary of Outcomes MRgFUS with IV microbubbles safely, reversibly, and repeatedly opened the BBB in all five mild-to-moderate AD patients (closure within 24 h) without serious clinical or radiographic adverse events and without clinically significant cognitive decline at 3 months; exploratory PET showed no group-wise change in beta‑amyloid. Successful FUS parameters included IV microbubbles with a ramp-test–determined cavitation threshold (~50% power), average sonication power ~4.6 W for stage 1 (mean ~3.6 sonications) and ~4.5 W for stage 2 (mean ~7.5 sonications), with targeted volumes (example 10×10×7 mm3) and real-time MR guidance.

Duration of biological effect 24 hours

Safety-related matter No serious clinical or radiographic adverse events were observed—no deaths, hemorrhages, swelling, or new neurologic deficits; BBB opening was safe, reversible, and closed within 24 h. Minor transient findings included a transient NPI-Q increase in one patient, headaches in one patient that resolved, and short-lived MRI hypointensities in two patients (possible microhemorrhage) that resolved by 24 h.

Brain Region

Ultrasound Parameters

Ultrasound instrument ExAblate Neuro (InSightec, Haifa); 1024 individual transducers, 220 kHz. Transducer aperture/diameter: None

FUS Frequency 220 kHz

FUS Mode pulsed

Pulse duration 2 ms

Duration of a single FUS session 50 s

Focal Characteristics Focal depth: None; Focal length: None; Aperture size: None

Treatment frequency multiple sessions

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