Focused Ultrasound Therapy
Focused ultrasound is an early-stage, non-invasive, 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. Where the beams converge, the ultrasound produces a variety of therapeutic effects without incisions or radiation.
Currently, there is no cure for Alzheimer’s and few disease modifying therapies. Potentially promising drug and antibody therapies are often limited by their inability to efficiently cross the blood-brain barrier (BBB), a naturally occurring barrier of cells that inhibits the diffusion of drugs or toxins into the central nervous system.
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.
Based on this preclinical evidence, a human trial investigating repeated, temporary opening of the BBB in patients with mild to moderate Alzheimer’s disease was recently completed. Read the press release >
- Focused ultrasound is non-invasive – 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 clinical trial investigating the repeated opening of the BBB in Alzheimer’s patients at Sunnybrook Health Sciences Centre in Toronto, Canada, has been published in Nature Communications. The trial aimed to assess the safety, feasibility and reversibility of BBB opening with focused ultrasound as well as the reproducibility of repeated BBB opening in human patients. Read the press release >
A Phase II trial at Sunnybrook Health Sciences Centre in Toronto, Canada, has begun. This 30-patient trial will investigate 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 third clinical trial in the US is using low-intensity focused ultrasound pulsation (LIFUP) to treat patients with early Alzheimer’s disease.
A clinical trial in Paris, France, is opening the BBB in patients with Alzheimer’s disease.
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. March 2019.
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.
Eguchi K, Shindo T, Ito K, Ogata T, Kurosawa R, Kagaya Y, Monma Y, Ichijo S, Kasukabe S, Miyata S, Yoshikawa T, Yanai K, Taki H, Kanai H, Osumi N, Shimokawa H. Whole-brain low-intensity pulsed ultrasound therapy markedly improves cognitive dysfunctions in mouse models of dementia - Crucial roles of endothelial nitric oxide synthase. Brain Stimul. 2018 May 22. pii: S1935-861X(18)30159-1. doi: 10.1016/j.brs.2018.05.012.
Nisbet RM, Götz J. Amyloid-β and Tau in Alzheimer's Disease: Novel Pathomechanisms and Non-Pharmacological Treatment Strategies. J Alzheimers Dis. 2018 Mar 16. doi: 10.3233/JAD-179907.
Hersh DS, Anastasiadis P, Mohammadabadi A, Nguyen BA, Guo S, Winkles JA, Kim AJ, Gullapalli R, Keller A, Frenkel V, Woodworth GF. MR-guided transcranial focused ultrasound safely enhances interstitial dispersion of large polymeric nanoparticles in the living brain. PLoS One. 2018 Feb 7;13(2):e0192240. doi: 10.1371/journal.pone.0192240. eCollection 2018.
Liu M, Jevtic S, Markham-Coultes K, Ellens NPK, O'Reilly MA, Hynynen K, Aubert I, McLaurin J. Investigating the efficacy of a combination Aβ-targeted treatment in a mouse model of Alzheimer's disease. Brain Res. 2018 Jan 1;1678:138-145. doi: 10.1016/j.brainres.2017.10.015. Epub 2017 Oct 21.
Silburt J, Lipsman N, Aubert I. Disrupting the blood-brain barrier with focused ultrasound: Perspectives on inflammation and regeneration. Proc Natl Acad Sci U S A. 2017 Aug 10. pii: 201710761. doi: 10.1073/pnas.1710761114.
Meng Y, Volpini M, Black S, Lozano AM, Hynynen K, Lipsman N. Focused ultrasound as a novel strategy for Alzheimer's disease therapeutics. Ann Neurol. 2017 Apr 10. doi: 10.1002/ana.24933.
Nisbet RM, Van der Jeugd A, Leinenga G, Evans HT, Janowicz PW, Götz J.Combined effects of scanning ultrasound and a tau-specific single chain antibody in a tau transgenic mouse model. Brain. 2017 Mar 4. doi: 10.1093/brain/awx052.
Burgess A, Hynynen K. Microbubble-Assisted Ultrasound for Drug Delivery in the Brain and Central Nervous System. Adv Exp Med Biol. 2016;880:293-308. doi: 10.1007/978-3-319-22536-4_16.
Click here for additional references from PubMed.