Noninvasive hippocampal blood-brain barrier opening in Alzheimer's disease with focused ultrasound.

The blood-brain barrier (BBB) presents a significant challenge for treating brain disorders. The hippocampus is a key target for novel therapeutics, playing an important role in Alzheimer's disease (AD), epilepsy, and depression. Preclinical studies have shown that magnetic resonance (MR)-guided low-intensity focused ultrasound (FUS) can reversibly open the BBB and facilitate delivery of targeted brain therapeutics. We report initial clinical trial results evaluating the safety, feasibility, and reversibility of BBB opening with FUS treatment of the hippocampus and entorhinal cortex (EC) in patients with early AD. Six subjects tolerated a total of 17 FUS treatments with no adverse events and neither cognitive nor neurological worsening. Post-FUS contrast MRI revealed immediate and sizable hippocampal parenchymal enhancement indicating BBB opening, followed by BBB closure within 24 h. The average opening was 95% of the targeted FUS volume, which corresponds to 29% of the overall hippocampus volume. We demonstrate that FUS can safely, noninvasively, transiently, reproducibly, and focally mediate BBB opening in the hippocampus/EC in humans. This provides a unique translational opportunity to investigate therapeutic delivery in AD and other conditions.

Rezai AR ，Ranjan M ，D'Haese PF ，Haut MW ，Carpenter J ，Najib U ，Mehta RI ，Chazen JL ，Zibly Z ，Yates JR ，Hodder SL ，Kaplitt M ... -  《-》

Focused ultrasound-mediated blood-brain barrier opening in Alzheimer's disease: long-term safety, imaging, and cognitive outcomes.

Rezai AR ，Ranjan M ，Haut MW ，Carpenter J ，D'Haese PF ，Mehta RI ，Najib U ，Wang P ，Claassen DO ，Chazen JL ，Krishna V ，Deib G ，Zibly Z ，Hodder SL ，Wilhelmsen KC ，Finomore V ，Konrad PE ，Kaplitt M ，Alzheimer’s Disease Neuroimaging Initiative ... -  《-》

Blood-Brain Barrier Opening with MRI-guided Focused Ultrasound Elicits Meningeal Venous Permeability in Humans with Early Alzheimer Disease.

Mehta RI ，Carpenter JS ，Mehta RI ，Haut MW ，Ranjan M ，Najib U ，Lockman P ，Wang P ，D'haese PF ，Rezai AR ... -  《-》

Focused ultrasound-mediated noninvasive blood-brain barrier modulation: preclinical examination of efficacy and safety in various sonication parameters.

Shin J ，Kong C ，Cho JS ，Lee J ，Koh CS ，Yoon MS ，Na YC ，Chang WS ，Chang JW ... -  《-》

Ultrasound with microbubbles improves memory, ameliorates pathology and modulates hippocampal proteomic changes in a triple transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease manifested by cognitive impairment. As a unique approach to open the blood-brain barrier (BBB) noninvasively and temporarily, a growing number of studies showed that low-intensity focused ultrasound in combination with microbubbles (FUS/MB), in the absence of therapeutic agents, is capable of ameliorating amyloid or tau pathology, concurrent with improving memory deficits of AD animal models. However, the effects of FUS/MB on both the two pathologies simultaneously, as well as the memory behaviors, have not been reported so far. Methods: In this study, female triple transgenic AD (3×Tg-AD) mice at eight months of age with both amyloid-β (Aβ) deposits and tau phosphorylation were treated by repeated FUS/MB in the unilateral hippocampus twice per week for six weeks. The memory behaviors were investigated by the Y maze, the Morris water maze and the step-down passive avoidance test following repeated FUS/MB treatments. Afterwards, the involvement of Aβ and tau pathology were assessed by immunohistochemical analysis. Neuronal health and phagocytosis of Aβ deposits by microglia in the hippocampus were examined by confocal microscopy. Further, hippocampal proteomic alterations were analyzed by employing two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) combined with mass spectrometry. Results: The three independent memory tasks were indicative of evident learning and memory impairments in eight-month-old 3×Tg-AD mice, which developed intraneuronal Aβ, extracellular diffuse Aβ deposits and phosphorylated tau in the hippocampus and amygdala. Following repeated FUS/MB treatments, significant improvement in learning and memory ability of the 3×Tg-AD mice was achieved. Amelioration in both Aβ deposits and phosphorylated tau in the sonicated hemisphere was induced in FUS/MB-treated 3×Tg-AD mice. Albeit without increase in neuron density, enhancement in axonal neurofilaments emerged from the FUS/MB treatment. Confocal microscopy revealed activated microglia engulfing Aβ deposits in the FUS/MB-treated hippocampus. Further, proteomic analysis revealed 20 differentially expressed proteins, associated with glycolysis, neuron projection, mitochondrial pathways, metabolic process and ubiquitin binding etc., in the hippocampus between FUS/MB-treated and sham-treated 3×Tg-AD mice. Conclusions: Our findings reinforce the positive therapeutic effects on AD models with both Aβ and tau pathology induced by FUS/MB-mediated BBB opening, further supporting the potential of this treatment regime for clinical applications.

Shen Y ，Hua L ，Yeh CK ，Shen L ，Ying M ，Zhang Z ，Liu G ，Li S ，Chen S ，Chen X ，Yang X ... -  《Theranostics》