. Noninvasive hippocampal blood-brain barrier opening in Alzheimer's disease with focused ultrasound. Proc Natl Acad Sci U S A. 2020 Apr 28;117(17):9180-9182. Epub 2020 Apr 13 PubMed.


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  1. A major challenge in treating brain diseases is presented by the blood-brain barrier (BBB), which constitutes an efficient barrier not only for toxins but also a wide range of therapeutic agents. In overcoming this impediment, ultrasound in combination with intravenously injected microbubbles has emerged as a powerful technology that allows for the selective brain uptake of blood-borne factors and therapeutic agents by transiently opening the BBB. Given that ultrasound parameters are highly tunable, the technique has been safely applied to achieve BBB opening in a range of species including mice, dogs, sheep, and macaques.

    Extending these findings to humans, Lipsman and colleagues have shown in a proof-of-concept Phase 1 study that safe BBB opening can be achieved in a limited non-eloquent white-matter area of the dorsolateral prefrontal cortex (Lipsman et al., 2018). Extending this work, the Kaplitt team now reports data from an ongoing multicenter Phase 2 trial demonstrating that a large volume of the BBB in the deep structure of the hippocampus and entorhinal cortex (14 percent to 71 percent, average 29 percent, of hippocampal volume) can be safely, reversibly, and repeatedly opened. Additional laboratories have either initiated clinical trials or are getting ready to embark on such a journey. The strategies vary and also include implanted ultrasound transducers (Carpentier et al., 2016). 

    Several questions remain. The first is whether opening of the BBB by itself is sufficient to clear any Alzheimer's pathology. We have shown that BBB opening is required for amyloid to be cleared (Leinenga et al., 2019), and our work further showed that dormant microglia become activated, presumably by unidentified blood-borne factors that enter the brain, with interstitial amyloid being taken up into microglial lysosomes (Leinenga et al., 2019Leinenga and Götz, 2015). The mechanism by which pathological tau is cleared differs. Here, neuronal autophagy is induced by therapeutic ultrasound (Pandit et al., 2019). Whether this approach will be sufficient in a human setting, or whether a combination therapy, such as with a tau antibody as pursued by us, is warranted, requires further study (Nisbet et al., 2017). 

    A second question relates to the treatment envelope and how this is linked to cognitive improvements. One could argue that one needs to target a brain area where neurodegeneration is initiated and assume that mitigates more widespread pathology that can be traced back to such a brain area. This is, in all likelihood, a too-simplistic viewpoint. It is more reasonable to assume that larger brain areas need to be targeted and that several treatment sessions will be required. Currently, however, the available technology does not allow for that.

    Having said that, it is exciting to see more and more data that ultrasound as a tunable modality can be applied safely to the brain, even in such a crucial brain area as the hippocampus with its fundamental role in memory functions.


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