Safety of a Strategy Combining Etanercept Administration With Repeated Contrast Ultrasound in Patients With Alzheimer's Disease

Alzheimer's disease (AD) is a clinico-pathological entity combining multiple and varied neuropathological lesions with characteristic abnormal accumulations (amyloid Beta (Aβ) plaques and neurofibrillary degeneration (NFD)), neuroinflammation, as well as neuronal and synaptic suffering. To date, only symptomatic treatments are available, with no proven effect on neuropathological lesions or on the clinical course of the disease. Anti-TNF alpha could be a therapeutic agent of choice in the treatment of central nervous sytem (CNS) diseases with an inflammatory component, such as AD. Unfortunately, their high molecular weight prevents them from passively crossing the blood brain barrier (BBB). In a pilot study published in 2006, etanercept was administered intrathecally to AD patients with encouraging clinical effects. Transient opening of the tight junctions between the endothelial cells of the BBB by delivering High Intensity Focalised Ultrasounds (HIFU) in combination with an intravenous injection of microbubbles is a strategy that could improve bioavailability. Studies suggest that the oscillation of microbubbles in the ultrasound field generates microcurrents that induce shear forces responsible for a transient opening of the BBB. Ultrasound can be focused or unfocused and open the BBB diffusely or selectively over defined regions of the brain. This technique was first used to open the BBB in humans in 2001. Transient opening of the BBB is also thought to modulate the immune response in the CNS, leading to a reduction in the intracerebral load of Aβ. In an Alzheimer's mouse model, several studies using ultrasound devices to open the BBB have shown a reduction in the intracerebral load of Aβ (up to 75%) and an improvement in the memory faculties and cognitive performance of the animals. In humans, two clinical trials have assessed the safety of using ultrasound-assisted BBB disruption devices in AD patients. These were the Sonocloud® (Carthera) and ExAblate® (