Optimal Treatment Conditions of the Low-intensity Pulsed Ultrasound Therapy for the Treatment of Alzheimer’s Disease -Applications from Mice to Humans-

Abstract

Abstract Background and Purpose We have previously developed a novel therapy with low-intensity pulsed ultrasound (LIPUS) that ameliorates cognitive decline through upregulation of endothelial nitric oxide synthase in mouse models of Alzheimer's disease (AD) and vascular dementia. We then conducted a randomized, double-blind, placebo-controlled (RCT) pilot trial for efficacy and safety of the whole-brain LIPUS therapy in patients with early AD. We demonstrated that the LIPUS therapy is safe and tends to suppress the cognitive decline in AD patients. We here report the findings of our basic experiments that we performed for the pilot trial in order to apply the whole-brain LIPUS therapy from mice to humans. Methods We performed basic experiments of the LIPUS therapy to identify the optimal treatment condition. First, by using human temporal bone, we examined the relationship between bone density/thickness and ultrasound transmittance. Next, based on the results of ultrasound transmittance, we further examined mRNA expression of vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2), and endothelial nitric oxide synthase (eNOS) in response to variable frequencies, duty cycles, and sound pressures. Results 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 ~ 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 the LIPUS therapy for 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. Conclusions We successfully found the optimal treatment conditions of the LIPUS therapy for the treatment of patients with AD.