Assessment of ultrasound-facilitated neurotherapeutics in Alzheimer's disease

Alzheimer’s disease (AD) kills 1 in 3 seniors (more than breast and prostate cancer combined), increased by 16% during the covid-19 pandemic in 2020 and is the costliest condition with an expected $355 billion in healthcare costs in 2021 and $1.1 trillion in 2050. Although some effective treatments are available, Alzheimer’s remains severely undertreated with several pharmacological compounds failing in clinical trials and/or practice over the past three decades. Focused Ultrasound (FUS), in conjunction with microbubbles, remains the sole technique that can induce localized blood-brain barrier (BBB) opening noninvasively, selectively and safely. Despite the fact that the technology was initially intended to open the BBB for drug delivery, our group was the first to report that BBB opening alone can lead to cognitive amelioration in primates. The safe BBB opening enabled by FUS can lead to an immune cascade that is in turn correlated with reduction of cognitive deficits and pathology. Prior to our studies reported herein, the immunotherapeutic potential of the FUS-mediated BBB opening was unknown. in this renewal study, we aim to determine 1) the currently unknown neuroprotective and immunotherapeutic mechanisms of FUS- mediated BBB opening as well as the duration of the aforementioned effects in multi-session BBB opening, 2) link cognitive improvement and/or immune response with synaptic density increase, 3) optimize the clinical FUS system for accurate hippocampal targeting in humans, 3) assess neuroprotection efficacy in asymptomatic AD subjects and 4) assess immunotherapeutic efficacy in symptomatic AD subjects. The underlying hypothesis is thus that FUS-mediated BBB opening alone leads to neuroprotective and immunotherapeutic with sustained mnemonic amelioration in AD. The multi-disciplinary team encompasses all critical specialty areas involved, such as ultrasound engineering as well as MRI, PET and AD pathology, neuroimmunology, cognitive and memory testing and mouse model development as they pertain to neuroscience and neurology. Following the proposed studies, this entirely noninvasive and cost efficient BBB opening technology will be translated in the clinical routine so as to harness its clinical potential in the treatment of Alzheimer’s.