Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-Machiachiachi, Aoba-Kuuu, Sendai, Miyagi, 980-8574, Japan.
Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering, Tohoku University, Sendai, Miyagi, Japan.
J Med Ultrason (2001). 2024 Jul;51(3):419-427. doi: 10.1007/s10396-024-01461-9. Epub 2024 May 2.
We previously developed a novel therapy with low-intensity pulsed ultrasound (LIPUS) that ameliorates cognitive decline through upregulation of endothelial nitric oxide synthase (eNOS) in mouse models of Alzheimer's disease (AD). In a randomized, double-blind, placebo-controlled pilot trial, we demonstrated that whole-brain LIPUS therapy is safe and tends to suppress the cognitive decline in early AD patients. We herein report the findings of our basic experiments that we performed for the pilot trial in order to apply whole-brain LIPUS therapy to humans, as well.
First, we examined the relationship between bone density/thickness and ultrasound transmittance using human temporal bone. Next, based on the results of ultrasound transmittance, we further examined mRNA expression of VEGF, FGF2, and eNOS in response to variable ultrasound frequencies, duty cycles, and sound pressures.
There was a significant correlation between bone thickness and transmittance (1.0 MHz, P < 0.001), while there was no significant correlation between bone density and transmittance (1.0 MHz, P = 0.421). At a frequency of 0.5 MHz, the optimum duty cycle was considered to be up to 20%. When the tissue amplitude was in the range of 0.05-0.5 MPa, VEGF, FGF2, and eNOS were significantly upregulated by LIPUS. Thus, the conditions necessary for LIPUS therapy for the human brain were identified as sound pressure just below the probe 1.3 MPa (tissue amplitude 0.15 MPa), duty cycle 5%, and frequency 0.5 MHz.
We successfully identified the optimal treatment conditions for LIPUS therapy for patients with AD.
我们之前开发了一种新的治疗方法，即低强度脉冲超声（LIPUS）治疗，通过在阿尔茨海默病（AD）小鼠模型中上调内皮型一氧化氮合酶（eNOS）来改善认知功能下降。在一项随机、双盲、安慰剂对照的初步试验中，我们证明了全脑 LIPUS 治疗是安全的，并倾向于抑制早期 AD 患者的认知能力下降。在此，我们报告了为该初步试验而进行的基础实验结果，以便将全脑 LIPUS 治疗应用于人类。
首先，我们用人颞骨检查了骨密度/厚度与超声透射率之间的关系。其次，根据超声透射率的结果，我们进一步研究了 VEGF、FGF2 和 eNOS 的 mRNA 表达，以响应不同的超声频率、占空比和声压。
骨厚度与透射率（1.0MHz）呈显著相关（P<0.001），而骨密度与透射率（1.0MHz）无显著相关（P=0.421）。在 0.5MHz 频率下，最佳占空比被认为高达 20%。当组织幅度在 0.05-0.5MPa 范围内时，LIPUS 可显著上调 VEGF、FGF2 和 eNOS。因此，确定了用于人脑 LIPUS 治疗的必要条件为探头下的声压 1.3MPa（组织幅度 0.15MPa），占空比 5%，频率 0.5MHz。
我们成功地确定了 AD 患者 LIPUS 治疗的最佳治疗条件。
