Focused Ultrasound Therapy
Focused ultrasound is an early-stage, noninvasive, therapeutic technology with the potential to improve the quality of life and decrease the cost of care for patients with Alzheimer’s disease. This novel technology focuses beams of ultrasonic energy precisely and accurately on targets deep in the brain without damaging surrounding normal tissue.
How it Works
Where the beams converge, focused ultrasound produces several therapeutic effects without incisions or radiation. One mechanism is the temporary opening of the blood-brain barrier (BBB), which may aid in the removal of beta amyloid or tao from the brain. In addition, potentially promising drug and antibody therapies are often limited by their inability to cross the BBB in high enough concentrations to have an impact in the brain, and opening the BBB may enable these therapeutic agents to access the brain. An additional mechanism is the ability to use neuromodulation to increase the activity of selected targets in patients with Alzheimer’s disease.
Promising preclinical studies have demonstrated the potential of focused ultrasound to enhance the delivery of therapeutic drugs or antibodies to the brain. Focused ultrasound in combination with microbubbles can safely open the BBB and enable enhanced delivery of anti-amyloid antibodies to the brain. Studies suggest that this method can reduce the number of plaques and improve cognition in Alzheimer’s disease models. Furthermore, focused ultrasound and microbubbles alone (no antibodies) have had similar effects in two different Alzheimer’s models.
- Focused ultrasound is noninvasive – no incisions, holes in the skull, electrodes in the brain – and therefore has reduced risk for infection and blood clots.
- Precise targeting minimizes damage to non-targeted healthy brain.
- Treatment can be a complement to drug therapy, enabling enhanced delivery of disease-modifying therapies into the brain via temporary opening of the blood-brain barrier.
A Phase II trial at Sunnybrook Health Sciences Centre in Toronto, Canada, is investigating the use of focused ultrasound to temporarily open the BBB in multiple regions of the brain.
A clinical trial in the US is opening the BBB with MR-guided focused ultrasound in patients with Alzheimer’s disease.
Another clinical trial in the US is opening the BBB with a neuronavigation device in patients with Alzheimer’s disease.
A clinical trial in the US is using low-intensity focused ultrasound pulsation (LIFUP) to treat patients with early Alzheimer’s disease.
An additional clinical trial in the US are treating patients with neurodegenerative dementia in Los Angeles, California. These studies are only recruiting patients by invitation.
Preclinical Laboratory Studies
Preclinical studies suggest focused ultrasound’s potential to reduce amyloid plaques and improve cognition in Alzheimer’s models. Active studies are assessing focused ultrasound-induced BBB opening to improve the delivery of:
- Anti-amyloid antibodies and other disease modifying drugs (Sunnybrook Health Sciences Centre; Columbia University; Queensland University – Australia; Brigham and Women’s Hospital)
- Anti-tau antibodies (Queensland University – Australia).
Suggested Reading: Focused Ultrasound for Alzheimer's Disease. January 2022.
Wasielewska JM, White AR. Focused Ultrasound-mediated Drug Delivery in Humans - a Path Towards Translation in Neurodegenerative Diseases. Pharm Res. 2022 Mar;39(3):427-439. doi: 10.1007/s11095-022-03185-2. Epub 2022 Mar 7.
Epelbaum S, Burgos N, Canney M, Matthews D, Houot M, Santin MD, Desseaux C, Bouchoux G, Stroer S, Martin C, Habert MO, Levy M, Bah A, Martin K, Delatour B, Riche M, Dubois B, Belin L, Carpentier A. Pilot study of repeated blood-brain barrier disruption in patients with mild Alzheimer's disease with an implantable ultrasound device. Alzheimers Res Ther. 2022 Mar 8;14(1):40. doi: 10.1186/s13195-022-00981-1.
Jeong H, Song IU, Chung YA, Park JS, Na SH, Im JJ, Bikson M, Lee W, Yoo SS. Short-Term Efficacy of Transcranial Focused Ultrasound to the Hippocampus in Alzheimer's Disease: A Preliminary Study. J Pers Med. 2022 Feb 9;12(2):250. doi: 10.3390/jpm12020250.
Kurz C, Walker L, Rauchmann BS, Perneczky R. Dysfunction of the blood-brain barrier in Alzheimer's disease: Evidence from human studies. Neuropathol Appl Neurobiol. 2022 Apr;48(3):e12782. doi: 10.1111/nan.12782. Epub 2022 Feb 2.
Luo K, Wang Y, Chen WS, Feng X, Liao Y, Chen S, Liu Y, Liao C, Chen M, Ao L. Treatment Combining Focused Ultrasound with Gastrodin Alleviates Memory Deficit and Neuropathology in an Alzheimer's Disease-Like Experimental Mouse Model. Neural Plast. 2022 Jan 13;2022:5241449. doi: 10.1155/2022/5241449. eCollection 2022.
Mi X, Du H, Guo X, Wu Y, Shen L, Luo Y, Wang D, Su Q, Xiang R, Yue S, Wu S, Gong J, Yang Z, Zhang Y, Tan X. Asparagine endopeptidase-targeted Ultrasound-responsive Nanobubbles Alleviate Tau Cleavage and Amyloid-beta Deposition in an Alzheimer's Disease Model. Acta Biomater. 2022 Jan 16:S1742-7061(22)00030-7. doi: 10.1016/j.actbio.2022.01.023.
Park SH, Baik K, Jeon S, Chang WS, Ye BS, Chang JW. Extensive frontal focused ultrasound mediated blood-brain barrier opening for the treatment of Alzheimer's disease: a proof-of-concept study. Transl Neurodegener. 2021 Nov 5;10(1):44. doi: 10.1186/s40035-021-00269-8.
Lakdawala D, Rashid MA, Ahmad FJ. Recent Advances in Targeted Drug Delivery Approaches using Lipidic and Polymeric Nanocarriers for the management of Alzheimer's Disease. Curr Pharm Des. 2021 Sep 27. doi: 10.2174/1381612827666210927163258.
Götz J, Richter-Stretton G, Cruz E. Therapeutic Ultrasound as a Treatment Modality for Physiological and Pathological Ageing Including Alzheimer's Disease. Pharmaceutics. 2021 Jul 1;13(7):1002. doi: 10.3390/pharmaceutics13071002.
Chan TG, Ruehl CL, Morse SV, Simon M, Rakers V, Watts H, Aprile FA, Choi JJ, Vilar R. Modulation of amyloid-beta aggregation by metal complexes with a dual binding mode and their delivery across the blood-brain barrier using focused ultrasound. Chem Sci. 2021 Jun 15;12(27):9485-9493. doi: 10.1039/d1sc02273c. eCollection 2021 Jul 14.
Xhima K, McMahon D, Ntiri E, Goubran M, Hynynen K, Aubert I. Intravenous and Non-invasive Drug Delivery to the Mouse Basal ForebrainUsing MRI-guided Focused Ultrasound. Bio Protoc. 2021 Jun 20;11(12):e4056. doi: 10.21769/BioProtoc.4056. eCollection 2021 Jun 20.
Sun T, Shi Q, Zhang Y, Power C, Hoesch C, Antonelli S, Schroeder MK, Caldarone BJ, Taudte N, Schenk M, Hettmann T, Schilling S, McDannold NJ, Lemere CA. Focused ultrasound with anti-pGlu3 Abeta enhances efficacy in Alzheimer's disease-like mice via recruitment of peripheral immune cells. J Control Release. 2021 Jun 26;336:443-456. doi: 10.1016/j.jconrel.2021.06.037.
Mehta RI, Carpenter JS, Mehta RI, Haut MW, Ranjan M, Najib U, Lockman P, Wang P, D'haese PF, Rezai AR. Blood-Brain Barrier Opening with MRI-guided Focused Ultrasound Elicits Meningeal Venous Permeability in Humans with Early Alzheimer Disease. Radiology. 2021 Jan 5:200643. doi: 10.1148/radiol.2021200643.
Lynch M, Heinen S, Markham-Coultes K, O'Reilly M, Van Slyke P, Dumont DJ, Hynynen K, Aubert I. Vasculotide restores the blood-brain barrier after focused ultrasound-induced permeability in a mouse model of Alzheimer's disease. Int J Med Sci. 2021 Jan 1;18(2):482-493. doi: 10.7150/ijms.36775. eCollection 2021.
Dubey S, Heinen S, Krantic S, McLaurin J, Branch DR, Hynynen K, Aubert I. Clinically approved IVIg delivered to the hippocampus with focused ultrasound promotes neurogenesis in a model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2020 Dec 22;117(51):32691-32700. doi: 10.1073/pnas.1908658117. Epub 2020 Dec 7.
D'Haese PF, Ranjan M, Song A, Haut MW, Carpenter J, Dieb G, Najib U, Wang P, Mehta RI, Chazen JL, Hodder S, Claassen D, Kaplitt M, Rezai AR. beta-Amyloid Plaque Reduction in the Hippocampus After Focused Ultrasound-Induced Blood-Brain Barrier Opening in Alzheimer's Disease. Front Hum Neurosci. 2020 Oct 7;14:593672. doi: 10.3389/fnhum.2020.593672. eCollection 2020.
Bobola MS, Chen L, Ezeokeke CK, Olmstead TA, Nguyen C, Sahota A, Williams RG, Mourad PD. Transcranial focused ultrasound, pulsed at 40 Hz, activates microglia acutely and reduces Aβ load chronically, as demonstrated in vivo. Brain Stimul. 2020 Apr 1;13(4):1014-1023. doi: 10.1016/j.brs.2020.03.016.
Rezai A, Ranjan M, D’Haese P, Haut M, Carpenter J, Najib U, Mehta R, Chazen J, Zibly Z, Yates J, Hodder S, Kaplitt M. Noninvasive hippocampal blood−brain barrier opening in Alzheimer’s disease with focused ultrasound. Proceedings of the National Academy of Sciences. Apr 2020, 202002571; DOI: 10.1073/pnas.2002571117
Liu Y, Gong Y, Xie W, Huang A, Yuan X, Zhou H, Zhu X, Chen X, Liu J, Liu J, Qin X. Microbubbles in combination with focused ultrasound for the delivery of quercetin-modified sulfur nanoparticles through the blood brain barrier into the brain parenchyma and relief of endoplasmic reticulum stress to treat Alzheimer's disease. Nanoscale. 2020 Mar 21;12(11):6498-6511. doi: 10.1039/c9nr09713a. Epub 2020 Mar 10.
Beisteiner R, Matt E, Fan C, Baldysiak H, Schönfeld M, Philippi Novak T, Amini A, Aslan T, Reinecke R, Lehrner J, Weber A, Reime U, Goldenstedt C, Marlinghaus E, Hallett M, Lohse-Busch H. Transcranial Pulse Stimulation with Ultrasound in Alzheimer's Disease-A New Navigated Focal Brain Therapy. Adv Sci (Weinh). 2019 Dec 23;7(3):1902583. doi: 10.1002/advs.201902583. eCollection 2020 Feb.
Lee YS, Choi Y, Park EJ, Kwon S, Kim H, Lee JY, Lee DS. Improvement of glymphatic-lymphatic drainage of beta-amyloid by focused ultrasound in Alzheimer’s disease model. bioRxiv 2020.01.24.918607; doi:https://doi.org/10.1101/2020.01.24.918607
Lee J, Chang WS, Shin J, Seo Y, Kong C, Song BW, Na YC, Kim BS, Chang JW. Non-invasively enhanced intracranial transplantation of mesenchymal stem cells using focused ultrasound mediated by overexpression of cell-adhesion molecules. Stem Cell Res. 2020 Jan 30;43:101726. doi: 10.1016/j.scr.2020.101726.
Weber-Adrian D, Kofoed RH, Chan JWY, Silburt J, Noroozian Z, Kügler S, Hynynen K, Aubert I. Strategy to enhance transgene expression in proximity of amyloid plaques in a mouse model of Alzheimer's disease. Theranostics. 2019 Oct 18;9(26):8127-8137. doi: 10.7150/thno.36718. eCollection 2019.
Nicodemus NE, Becerra S, Kuhn TP, Packham HR, Duncan J, Mahdavi K, Iovine J, Kesari S, Pereles S, Whitney M, Mamoun M, Franc D, Bystritsky A, Jordan S. Focused transcranial ultrasound for treatment of neurodegenerative dementia. Alzheimers Dement (N Y). 2019 Aug 8;5:374-381. doi: 10.1016/j.trci.2019.06.007. eCollection 2019.
Karakatsani ME, Kugelman T, Ji R, Murillo M, Wang S, Niimi Y, Small SA, Duff KE, Konofagou EE. Unilateral Focused Ultrasound-Induced Blood-Brain Barrier Opening Reduces Phosphorylated Tau from The rTg4510 Mouse Model. Theranostics. 2019 Jul 13;9(18):5396-5411. doi: 10.7150/thno.28717. eCollection 2019.
Meng Y, MacIntosh BJ, Shirzadi Z, Kiss A, Bethune A, Heyn C, Mithani K, Hamani C, Black SE, Hynynen K, Lipsman N. Resting state functional connectivity changes after MR-guided focused ultrasound mediated blood-brain barrier opening in patients with Alzheimer's disease. Neuroimage. 2019 Jun 26;200:275-280. doi: 10.1016/j.neuroimage.2019.06.060.
Poon CT, Shah K, Lin C, Tse R, Kim KK, Mooney S, Aubert I, Stefanovic B, Hynynen K. Time course of focused ultrasound effects on β-amyloid plaque pathology in the TgCRND8 mouse model of Alzheimer's disease. Sci Rep. 2018 Sep 19;8(1):14061. doi: 10.1038/s41598-018-32250-3.
Hsu PH, Lin YT, Chung YH, Lin KJ, Yang LY, Yen TC, Liu HL. Focused Ultrasound-Induced Blood-Brain Barrier Opening Enhances GSK-3 Inhibitor Delivery for Amyloid-Beta Plaque Reduction. Sci Rep. 2018 Aug 27;8(1):12882. doi: 10.1038/s41598-018-31071-8.
Lipsman N, Meng Y, Bethune AJ, Huang Y, Lam B, Masellis M, Herrmann N, Heyn C, Aubert I, Boutet A, Smith GS, Hynynen K, Black SE. Blood-brain barrier opening in Alzheimer's disease using MR-guided focused ultrasound. Nat Commun. 2018 Jul 25;9(1):2336. doi: 10.1038/s41467-018-04529-6.
Click here for additional references from PubMed.