Scanning ultrasound-mediated memory and functional improvements do not require amyloid-β reduction
Gerhard Leinenga, Xuan Vinh To, Liviu-Gabriel Bodea, Jumana Yousef, Gina Richter-Stretton, Tishila Palliyaguru, Antony Chicoteau, Laura Dagley, Fatima Nasrallah, Jürgen Götz
Molecular Psychiatry 2024 · 10.1038/s41380-024-02509-5
Abstract
A prevalent view in treating age-dependent disorders including Alzheimer's disease (AD) is that the underlying amyloid plaque pathology must be targeted for cognitive improvements. In contrast, we report here that repeated scanning ultrasound (SUS) treatment at 1 MHz frequency can ameliorate memory deficits in the APP23 mouse model of AD without reducing amyloid-β (Aβ) burden. Different from previous studies that had shown Aβ clearance as a consequence of blood-brain barrier (BBB) opening, here, the BBB was not opened as no microbubbles were used. Quantitative SWATH proteomics and functional magnetic resonance imaging revealed that ultrasound induced long-lasting functional changes that correlate with the improvement in memory. Intriguingly, the treatment was more effective at a higher frequency (1 MHz) than at a frequency within the range currently explored in clinical trials in AD patients (286 kHz). Together, our data suggest frequency-dependent bio-effects of ultrasound and a dissociation of cognitive improvement and Aβ clearance, with important implications for the design of trials for AD therapies.
Abstract via europepmc.
Exposures
Exposure 1: HighF: 1 MHz scanning ultrasound (SUS-only) to whole brain
Target: whole brain or unfocused — “whole brain (5x6 grid of scanning spots)”
Device: Philips Research · Philips Research · Therapy Imaging Probe System (TIPS), 8-element annular array ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 1,000 | ✓✓✓ |
| Pulse duration (ms) | 10 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 10 | ✓✓✓ |
| Duty cycle (%) | not reportedpulse duration × PRF gives 10% | |
| Sonication duration (s) | 6 | ✓✓✓ |
| Free-field pressure (kPa) | 700 | ✓✓✓ |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | deratingsingle value | |
| In-situ pressure (kPa) | 570 | ✓✓✓ |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported |
Whole-brain exposure achieved by scanning a 5x6 grid of spots (1.5 mm spacing) with the annular-array TIPS transducer; mice received 8 once-per-week treatments; sham mice received anaesthesia and transducer placement without power.
Exposure 2: LowF: 286 kHz scanning ultrasound (SUS-only) to whole brain
Target: whole brain or unfocused — “whole brain (4-spot grid)”
Device: Sonic Concepts · Sonic Concepts, Bothell WA, USA · H-117 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 286 | ✓✓✓ |
| Pulse duration (ms) | 10 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 10 | ✓✓✓ |
| Duty cycle (%) | not reportedpulse duration × PRF gives 10% | |
| Sonication duration (s) | 6 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | ⚑ |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | deratingsingle value | |
| In-situ pressure (kPa) | 570 | ✓✓✓ |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported |
Whole-brain exposure achieved with a 4-spot grid (6 mm spacing) using the H-117 transducer; mice received 8 once-per-week treatments; sham mice received anaesthesia and transducer placement without power.
Flags from extraction
n_subjects— Only per-group sizes are given for the two ultrasound-treated groups (HighF N=12, LowF N=11); no combined total exposed to ultrasound is stated, so group sizes are listed rather than summed. The sham (N=12) and WT (N=12) groups were not exposed to real ultrasound and are excluded.exposures[1].free_field.pressure_kpa— For the LowF condition the paper calls the water-measured 0.57 MPa value 'in situ' (assuming negligible skull attenuation) rather than free-field, so it was placed in in_situ rather than free_field despite being measured in water.