Time course of focused ultrasound effects on β-amyloid plaque pathology in the TgCRND8 mouse model of Alzheimer's disease.

Authors: Poon CT, Shah K, Lin C, Tse R, Kim KK, Mooney S, Aubert I, Stefanovic B, Hynynen K

Previous studies have demonstrated that temporarily increasing the permeability of the blood-brain barrier using focused ultrasound can reduce β-amyloid plaque load and improve cognitive function in animal models of Alzheimer's disease. However, the underlying mechanism and duration for which the effects of one treatment persists for are unknown. Here, we used in vivo two-photon fluorescence microscopy to track changes in β-amyloid plaque sizes in the TgCRND8 mouse model of Alzheimer's disease after one focused ultrasound treatment. We found that one treatment reduced plaques to 62 ± 16% (p ≤ 0.001) of their original volume two days post-sonication; this decrease in size persisted for two weeks. We then sought to evaluate the effectiveness of biweekly focused ultrasound treatments using magnetic resonance imaging-guided focused ultrasound treatments. Three to five biweekly treatments resulted in a 27 ± 7% (p ≤ 0.01) decrease in plaque number and 40 ± 10% (p ≤ 0.01) decrease in plaque surface area compared to untreated littermates. This study demonstrates that one focused ultrasound treatment reduces the size of existing β-amyloid plaques for two weeks, and that repeated biweekly focused ultrasound treatments is an effective method of reducing β-amyloid pathology in moderate-to-late stages of Alzheimer's disease.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To evaluate whether single and repeated MR-guided focused ultrasound treatments reduce the size and burden of β-amyloid plaques and how long a single treatment's effects persist in the TgCRND8 mouse model of Alzheimer’s disease.

Animal model / Human subject Mouse, TgCRND8, None, None

Disease model Alzheimer's disease

MRI or image guidance method MRI-guided focused ultrasound

Outcomes and Safety

Summary of Outcomes A single focused ultrasound (FUS) BBB-opening treatment reduced existing β‑amyloid plaque volume to ~62% of baseline at 2 days with reductions persisting up to two weeks. Repeated MR‑guided, microbubble‑mediated FUS delivered biweekly (3–5 treatments, with acoustic control) decreased hippocampal plaque number by ~27% and plaque surface area by ~40% versus untreated controls.

Duration of biological effect 2 weeks

Safety-related matter Multiple FUS treatments were well-tolerated in old TgCRND8 mice: mortality was low and did not differ by genotype or treatment, and body weights remained stable. The authors report no evidence of treatment-related edema, vacuolations, neuronal loss, or erythrocyte extravasation and note that cerebral microbleeds are a literature concern but are rarely observed after FUS.

Brain Region

Visualization unavailable

Ultrasound Parameters

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

Treatment frequency both single and multiple sessions

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