Focused Ultrasound Therapy
Focused ultrasound is a rapidly evolving, 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 clinical trial in West Virginia is combining opening of the BBB with Aducanumab in patients with early cognitive disability or Alzheimer’s disease.
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.
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: Transforming treatment of Neurodegenerative Diseases. August 2022
Suggested Reading: Focused Ultrasound for Alzheimer’s Disease. January 2022.
Bajracharya R, Cruz E, Götz J, Nisbet RM. Ultrasound-mediated delivery of novel tau-specific monoclonal antibody enhances brain uptake but not therapeutic efficacy. J Control Release. 2022 Sep;349:634-648. doi: 10.1016/j.jconrel.2022.07.026. Epub 2022 Jul 27.
Xhima K, Markham-Coultes K, Hahn Kofoed R, Saragovi HU, Hynynen K, Aubert I. Ultrasound delivery of a TrkA agonist confers neuroprotection to Alzheimer-associated pathologies. Brain. 2022 Aug 27;145(8):2806-2822. doi: 10.1093/brain/awab460.
Dörl G, Matt E, Beisteiner R. Functional Specificity of TPS Brain Stimulation Effects in Patients with Alzheimer’s Disease: A Follow-up fMRI Analysis. Neurol Ther. 2022 Sep;11(3):1391-1398. doi: 10.1007/s40120-022-00362-8. Epub 2022 May 28.
Bathini P, Sun T, Schenk M, Schilling S, McDannold NJ, Lemere CA. Acute Effects of Focused Ultrasound-Induced Blood-Brain Barrier Opening on Anti-Pyroglu3 Abeta Antibody Delivery and Immune Responses. Biomolecules. 2022 Jul 6;12(7):951. doi: 10.3390/biom12070951.
Bajracharya R, Cruz E, Götz J, Nisbet RM. Ultrasound-mediated delivery of novel tau-specific monoclonal antibody enhances brain uptake but not therapeutic efficacy. J Control Release. 2022 Jul 27;349:634-648. doi: 10.1016/j.jconrel.2022.07.026.
Tatulian SA. Challenges and hopes for Alzheimer’s disease. Drug Discov Today. 2022 Apr;27(4):1027-1043. doi: 10.1016/j.drudis.2022.01.016. Epub 2022 Feb 1.
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.
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 Mar 15;141:388-397. doi: 10.1016/j.actbio.2022.01.023. Epub 2022 Jan 16.
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.
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.
Click here for additional references from PubMed.