Low-intensity, non-targeted transcranial ultrasound for enhancing glymphatic function in Alzheimer's disease treatment - Summary Statement Alzheimer’s disease (AD) is a growing public health crisis, affecting 6.7 million older Americans, with projections to double by 2050. The glymphatic system, responsible for clearing waste products such as amyloid beta, plays a crucial role in disease progression. However, it struggles to clear larger molecules, like amyloid plaques, worsening the condition. Current anti- amyloid therapies often cause amyloid-related imaging abnormalities (ARIA), resulting in brain swelling, neuropsychiatric symptoms, and vascular damage, which further impair glymphatic function. While lifestyle changes like adequate sleep, hydration, and exercise support glymphatic function, stronger evidence is needed to validate their effectiveness. Non- invasive methods like low-level transcranial stimulation and photobiomodulation have been explored but are limited by their inability to penetrate the skull effectively, highlighting the need for more effective transcranial solutions. Low-Intensity Transcranial Focused Ultrasound (tFUS) offers a promising approach by temporarily opening the blood-brain barrier (BBB) to aid drug delivery and potentially accelerate glymphatic flow. However, in AD patients with a compromised BBB, further increasing permeability could be detrimental. Our research aims to develop an alternative tFUS method that modulates glymphatic flow without opening the BBB, achieving therapeutic outcomes comparable to or better than traditional tFUS BBB opening way. This method, termed Ultrasonic Modulation of Glymphatic Function (UMGF), uses specific tFUS parameters to enhance glymphatic flow without disrupting the BBB. Innovative aspects of this proposal include (1) a novel mathematical model based on reaction-diffusion partial differential equations, incorporating longitudinal in-vivo and ex-vivo rat imaging data, aims to optimize UMGF for better clearance, and (2) the UMGF treatment approach, offering a unique alternative to traditional tFUS by enhancing glymphatic function without the need to open the BBB or use MRI guidance, making it cost-effective and accessible for clinical use. The main aims of this study are to (1) develop a mathematical model to optimize UMGF for effective glymphatic clearance, and (2) assess its effects on cognitive function and histopathological changes in 5XFAD AD mouse model exhibiting amyloid pathology. We hypothesize that UMGF will enhance glymphatic clearance, reduce amyloid plaque accumulation, decrease ARIA-related pathology, and improve cognitive function. The outcomes of this research could provide a safer, non-invasive therapeutic strategy for AD, especially for patients with compromised BBB integrity. Additionally, UMGF may have broader applications in conditions associated with glymphatic dysfunction, such as traumatic brain injury, sleep disorders, and cancer. This study, conducted at North Carolina A&T State University, will leverage the team's expertise in tFUS (Aryal), neuroscience (Braun and Niere), and mathematical modeling (Hinow) to optimize and evaluate UMGF as a potential treatment for AD.
