Tohoku J. Exp. Med., 2022 November, 258(3)

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,^1,2 Tomohiko Shindo,¹ Aiko Ishiki,³ Naoki Tomita,³ Sadamitsu Ichijyo,¹ Tasuku Watanabe,¹ Takashi Nakata,¹ Kumiko Eguchi,¹ Yoku Kikuchi,¹ Takashi Shiroto,¹ Jun Takahashi,¹ Satoshi Yasuda¹ and Hiroyuki Arai³

¹Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
²Graduate School, International University of Health and Welfare, Narita, Chiba, Japan
³Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, Japan

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.

Keywords —— Alzheimer’s disease; dementia; low-intensity pulsed ultrasound; nitric oxide; nitric oxide synthase

© 2022 Tohoku University Medical Press

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Tohoku J. Exp. Med 2022, 258, 167-175.

Correspondence: Hiroaki Shimokawa, M.D., Ph.D., Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.

e-mail: shimo@cardio.med.tohoku.ac.jp