A Pilot Study of Whole-Brain Low-Intensity Pulsed Ultrasound Therapy for Early Stage of Alzheimer’s Disease (LIPUS-AD): A Randomized, Double-Blind, Placebo-Controlled Trial
Hiroaki Shimokawa, Tomohiko Shindo, Aiko Ishiki, Naoki Tomita, Sadamitsu Ichijyo, Tasuku Watanabe, Takashi Nakata, Kumiko Eguchi, Yoku Kikuchi, Takashi Shiroto, Jun Takahashi, Satoshi Yasuda, Hiroyuki Arai
The Tohoku Journal of Experimental Medicine 2022 · 10.1620/tjem.2022.j078
Abstract
The prevalence of Alzheimer's disease (AD) has been rapidly increasing worldwide. We have developed a novel angiogenic therapy with low-intensity pulsed ultrasound (LIPUS), which is effective and safe in animal models of AD and vascular dementia. We performed two trials of LIPUS therapy for AD (mild cognitive impairment due to AD and mild AD); a roll-in open trial for safety, and a randomized, double-blind, placebo-controlled (RCT) trial for efficacy and safety. The LIPUS therapy was performed for whole brain through the bilateral temporal bones for one hour 3 times a week as one session under the special conditions (1.3 MPa, 32 cycles, 5% duty cycle) we identified. The LIPUS therapy was performed for one session in the roll-in trial, and 6 sessions in the RCT trial with 3-month intervals for 1.5 years. The primary endpoint was ADAS-J cog scores. The RCT trial was terminated prematurely due to the COVID-19 pandemic. In the roll-in trial (N = 5), no adverse effects were noted. In the RCT trial (N = 22), the worsening of ADAS-J cog scores tended to be suppressed in the LIPUS group compared with the placebo group at week 72 (P = 0.257). When responders were defined as those with no worsening of ADAS-J cog scores at week 72, the prevalence was 50% (5/10) and 0% (0/5) in the LIPUS and placebo groups, respectively (P = 0.053). No adverse effects were noted. These results suggest that the LIPUS therapy is safe and tends to suppress cognitive impairment although a next pivotal trial with a large number of subjects is warranted.
Abstract via europepmc.
Exposures
Exposure 1: Whole-brain LIPUS via bilateral temporal bones
Target: whole brain or unfocused — “whole brain through the bilateral temporal bones”
Device: not reported
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 500 | ✓✓✓ |
| Pulse duration (ms) | 0.064 | ✓✓✓⚑ |
| Pulse repetition frequency (Hz) | 781 | ✓✓✓ |
| Duty cycle (%) | 5pulse duration × PRF gives 4.998% | ✓✓✓ |
| Sonication duration (s) | 1,200 | ✓✓✓⚑ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not reported | |
| In-situ pressure (kPa) | 150, 190swept | ✓✓✓ |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported | |
| Pressure, domain unspecified (kPa) | 500, 1,000, 1,300swept | ✓✓✓⚑ |
LIPUS 20 min, 3 times with a 5 min interval each time; one session is therapy every other day for 3 days; 32 cycles per pulse, duty cycle 5%, PRF 781 Hz (interval 1.28 msec). RCT: 6 sessions at 3-month intervals.
Flags from extraction
n_subjects— Roll-in trial N = 5 and RCT enrolled N = 22 (19 analysed); total exposed not stated, group sizes listed.exposures[0].unspecified_domain.pressure_kpa— Roll-in escalated 0.5, 1.0, 1.3 MPa; RCT used 1.3 MPa. Domain not stated (the probe design text discusses Ispta values in MPa below the skull and at depth, not used here).exposures[0].timing.pulse_duration_ms— Pulse described as 32 cycles at 0.5 MHz; a pulse duration in ms is not stated, so left not_reported.exposures[0].timing.sonication_duration_s— 20 min x 3 with 5 min intervals; unclear whether each 20 min is one uninterrupted train. The abstract also says 'one hour 3 times a week as one session'.exposures[0].device— Convex diffusion-type probe developed by the group; maker not named.