Table 1. The use of focused ultrasound (FUS) to open the blood-brain barrier (BBB) in the treatment of Alzheimer's disease (AD): a list of pre-clinical studies analyzed and their results.

Author, year	Animal model	Results
Raymond et al., 20088	Mouse	Sonication, with temporary interruption of the BBB, allowed the entry of therapeutic agents and molecular imaging agents.
Choi et al., 20089	Mouse	FUS allowed the opening of BBB and the entry of molecules by microbubbles. The extent of the opening and closing time of the BBB depend on the region of the brain.
Jordão et al., 201010	Mouse	FUS associated with administration of anti-b-amyloid antibody (BAM 10) in transgenic mice (TgCRND8) promoted a significant reduction of b-amyloid peptide plaques.
Konofagou et al., 201211	Mouse	FUS with microbubbles targeting the hippocampus demonstrated increased BBB permeability by at least two orders of magnitude. Therapeutic molecules that improve cognition and brain aging successfully crossed the BBB. BBB permeability depended on the pressure used and the size of the microbubbles.
Jordão et al., 201312	Mouse	After a single FUS session, b-amyloid plaque size was reduced by 20%, while the total plaque surface was reduced by 13%. Histological studies showed the entry of endogenous antibodies into the b-amyloid plaque and the activation of microglia and astrocytes.
Burgess et al., 201413	Mouse	After the use of FUS, the permeability of the vessels of the transgenic mice (TgCRND8) and non-transgenic were compared. Transgenic vessels with amyloid plaques proved much more impermeable and had a smaller diameter after FUS.
Burgess et al., 201414	Mouse	After sonication, there was a 99% improvement in the spatial memory activity of transgenic mice (TgCRND8), as well as a 250% increase in the number of new neurons in the hippocampus with longer and arborized dendrites.
Nisbet et al., 201715	Mouse	Administration of 2N tau isoform-specific single chain antibody fragment (RN2N), combined with the use of FUS in scanner mode, significantly improved brain distribution and efficacy.
Alecou, Giannakou & Damianou 201716	Rabbit	Administration of antibodies to b-amyloid protein reduced the number of plaques from 200 to 170/cm2, while the concomitant use of FUS and antibodies decreased levels from 200 to 78/cm2. Repeated application of FUS increased the reduction of b-amyloid plaques.
O'Reilly et al., 201717	Rat	A study was performed to analyze the relationship between the opening volume of BBB and its closing time. Closing time of the BBB was independent of opening volume. It was suggested that larger volume opening can be done safely.
O'Reilly et al., 201718	Dog	The opening of the BBB from a complete hemisphere of the brain by sonication was well tolerated by beagles (9-11 years old), indicating the clinical safety of the method. There was no significant reduction in b-amyloid load. Further studies are needed to determine whether there are benefits in natural pathologies associated with b-amyloid plaques.
Liu et al., 201819	Mouse	This study aimed to analyze the association between FUS with anti-b-amyloid antibody (BAM-10) and scyllo-inositol. There was no summation of the benefits of FUS with BAM-10 associated with scyllo-inositol. Both were efficient alone or combined, reducing b-amyloid plaque and increasing astrocyte activation, but were not more effective when used together.
Hsu et al, 201820	Mouse	This study aimed to evaluate whether the use of FUS-induced BBB opening could enhance the delivery of GSK-3 inhibitor, which would promote an additive effect on b-amyloid clearance, as well as reduce its synthesis in transgenic AD mice models. The procedure was performed unilaterally, using the contralateral hemisphere as a reference. Immunohistochemistry showed that GSK-3 inhibitors reduced GSK-3 activity by up to 61.3% with the addition of FUS, and autoradiography showed significant b-amyloid reduction.
Eguchi et al, 201821	Mouse	Therapeutic FUS in the hippocampus exerts a neuroprotective action on dementia. The study evaluated the efficacy and safety of LIPUS throughout the brain in mice with 2 types of dementia: vascular dementia and Alzheimer's dementia. In both models, LIPUS therapy substantially improved cognitive deficits (labyrinth Y test and/or passive evasion test), improved cerebral blood flow and regulated endothelial related genes.
Xu et al, 201822	Mouse	The failure of many clinical trials suggests inefficacy in the treatment of AD using only one target. This study used multiple targets through a nano-drug protoporphyrin IX (PX) modified oxidized mesoporous carbon (OMCN) nanospheres (PX @ OMCN @ PEG (OP) @RVGs), which appears to be an efficient inhibitor of phosphorylated tau. Also, PX, together with FUS, significantly reduced b-amyloid plaque aggregation.

FUS: Focused Ultrasound; BBB: Blood-Brain Barrier; GSK-3:Glycogen synthase kinase 3.