Focused ultrasound as a non-invasive method with therapeutic potential in patients with Alzheimer’s disease

Kovalenko E.A.; Makhnovich E.V.; Osinovskaya N.A.; Bogolepova A.N.

doi:https://doi.org/10.17116/jnevro202212210138

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Abstract:

Alzheimer’s disease (AD) is a common, progressive neurodegenerative disease characterized by abnormal deposition of β-amyloid (Aβ) and hyperphosphorylated tau protein. Despite the fact that biomarkers and methods of treating AD are currently being actively studied, there is still no therapy that can significantly reduce the progression of this disease. Therefore, the search for therapeutic disease-modifying strategies is becoming increasingly popular. One such strategy is the use of focused ultrasound (FUS) under MRI guidance using a contrast agent (microbubbles). Under the influence of low-intensity FUS, the blood-brain barrier (BBB) is temporarily opened, which is the main obstacle to the effective delivery of therapeutic compounds to the brain, imposing dimensional and biochemical restrictions on the passage of molecules. One of the processes associated with AD is BBB dysfunction, and therefore the study of the effects of FUS in patients with AD is of interest. The literature data show the effectiveness of FUS in animal models of AD. The researchers attribute the effectiveness of the method to the fact that exposure to FUS induces the opening of BBB and reduces the number of amyloid plaques. It has also been demonstrated that FUS can facilitate the delivery of therapeutic drugs to the brain. This allows considering FUS as a new non-invasive method of treatment. Further research is needed to assess the effectiveness of this method in patients with AD.

Keywords:

Alzheimer’s disease

focused ultrasound

blood-brain barrier

beta-amyloid

tau-protein

treatment

Authors:

Kovalenko E.A.

Pirogov Russian National Research Medical University;
Federal Center of Brain Research and Neurotechnologies

ORCID: 0000-0003-0828-9868

Makhnovich E.V.

Pirogov Russian National Research Medical University;
Federal Center of Brain Research and Neurotechnologies

ORCID: 0000-0002-8606-5715

Osinovskaya N.A.

Federal Center of Brain Research and Neurotechnologies

ORCID: 0000-0003-2313-571X

Bogolepova A.N.

Pirogov Russian National Research Medical University;
Federal Center of Brain Research and Neurotechnologies of the Federal Medical Biological Agency

SPIN RSCI: 6775-0279
Scopus AuthorID: 6602240836
ORCID: 0000-0002-6327-3546

Received:

19.04.2022

Accepted:

20.04.2022

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References:

Koberskai NN. Bolezn Alzheimera. Nevrologia. Neiropsihiatria, psihosomatica. 2019;11(35):52. (In Russ.). https://doi.org/10.14412/2074-2711-2019-3S-52-60
Bogolepova AN, Zhuravleva AN, Makhnovich EV. Perspectives of the diagnosis of Alzheimer’s disease using optic coherent tomography. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2017;117(9):112-117. (In Russ.). https://doi.org/10.17116/jnevro201711791112-117
Yiannopoulou KG, Papageorgiou SG. Current and future treatments in Alzheimer disease: an update. Journal of central nervous system disease. 2020;12:1179573520907397. https://doi.org/10.1177/1179573520907397
Bogolepova AN. A contemporary view of the possibilities of preventing dementia. Medicinskij sovet. 2019;(18):48-54. (In Russ.). https://doi.org/10.21518/2079-701X-2019-18-52-58
Vassar R, Citron M. Abeta-generating enzymes: recent advances in beta- and gamma-secretase research. Neuron. 2000;27(3):419-422. https://doi.org/10.1016/s0896-6273(00)00051-9.
Pilipovich AA, Danilov AB. New strategies for diagnosis and treatment of Alzheimer’s disease: monoclonal antibodies to beta-amyloid. Medical alphabet. 2019;1(2):35-42. (In Russ.). https://doi.org/10.33667/2078-5631-2019-1-2(377)-35-42
Wolf S, Seehaus B, Minol K, Gassen HG. The blood-brain barrier: a specialty of cerebral microcirculation systems. Die Naturwissenschaften. 1996;83(7):302-311.
Sweeney MD, Sagare AP, Zlokovic BV. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol. 2018;14(3):133-150. https://doi.org/10.1038/nrneurol.2017.188
Nelson AR, Sweeney MD, Sagare AP, Zlokovic BV. Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer’s disease. Biochim Biophys Acta. 2016;1862(5):887-900. https://doi.org/10.1016/j.bbadis.2015.12.016
Montagne A, Zhao Z, Zlokovic BV. Alzheimer’s disease: A matter of blood-brain barrier dysfunction? J Exp Med. 2017;214(11):3151-3169. https://doi.org/10.1084/jem.20171406
Jordão JF, Thévenot E, Markham-Coultes K, et al. Amyloid-β plaque reduction, endogenous antibody delivery and glial activation by brain-targeted, transcranial focused ultrasound. Exp Neurol. 2013;248:16-29. https://doi.org/10.1016/j.expneurol.2013.05.008
Bien-Ly N, Boswell CA, Jeet S, et al. Lack of Widespread BBB Disruption in Alzheimer’s Disease Models: Focus on Therapeutic Antibodies. Neuron. 2015;88(2):289-297. https://doi.org/10.1016/j.neuron.2015.09.036
Souza RM, da Silva ICS, Delgado ABT, et al. Focused ultrasound and Alzheimer’s disease A systematic review. Dement Neuropsychol. 2018;12(4):353-359. https://doi.org/10.1590/1980-57642018dn12-040003
Zinchenco EM, Klimova MM, Shirocova AA, et al. Izmenenia pronizaemosti gematoinzefalichescogo bariera pri razvitii bolezni Alzheimera. Izvestia Saratovscogo Yniversiteta. NoSeria Himii. Biologii. Icologii. 2019;19(4):427-439. (In Russ.). https://doi.org/10.18500/1816-9775-2019-19-4-427-439
Izadifar Z, Babyn P, Chapman D. Mechanical and biological effects of ultrasound: A review of present knowledge. Ultrasound in medicine & biology. 2017;43(6):1085-1104. https://doi.org/10.1016/j.ultrasmedbio.2017.01.023
O’Brien W. Ultrasound-biophysics mechanisms. Progress in biophysics and molecular biology. 2007;93:212-255. https://doi.org/10.1016/j.pbiomolbio.2006.07.010
Clement GT, White J, Hynynen K. Investigation of a large-area phased array for focused ultrasound surgery through the skull. Physics in Medicine &Biology. 2000;45(4):1071.
Tyrnicov VM, Gysha AO. Visocointensivnie focusirovannii yltrazvuk v funczionalnoi neurohirurgii. Anali klinichescoi b experementalnoi nevrologii. 2016;10(4):52-57. (In Russ.).
Galkin MV. The use of transcranial focused ultrasound in CNS diseases. Zhurnal Voprosy Neirokhirurgii Imeni N.N. Burdenko. 2016;80(2):108-118. (In Russ.). https://doi.org/10.17116/neiro2016802108-118
Holyavin AI. Tekhnicheskie, klinicheskie i ekonomicheskie aspekty lechebnogo transkranial’nogo fokusirovannogo ul’trazvuka. Byulleten’ Nacional’nogo obshchestva po izucheniyu bolezni Parkinsona i rasstrojstv dvizhenij. 2019;1:17-24. (In Russ.).
Chang WS, Jung HH, Kweon EJ, et al. Unilateral magnetic resonance guided focused ultrasound thalamotomy for essential tremor: practices and clinicoradiological outcomes. J Neurol Neurosurg Psychiatry. 2015;86(3):257-264. https://doi.org/10.1136/jnnp-2014-307642
Gasca-Salas C, Fernández-Rodríguez B, Pineda-Pardo JA, et al. Blood-brain barrier opening with focused ultrasound in Parkinson’s disease dementia. Nature communications. 2021;12(1):1-7. https://doi.org/10.1038/s41467-021-21022-9
Jung NY, Park CK, Chang WS, et al. Effects on cognition and quality of life with unilateral magnetic resonance-guided focused ultrasound thalamotomy for essential tremor. Neurosurgical Focus. 2018;44(2):E8. https://doi.org/10.3171/2017.11.FOCUS17625
Schreglmann SR, Bauer R, Hägele-Link S, et al. Unilateral cerebellothalamic tract ablation in essential tremor by MRI-guided focused ultrasound. Neurology. 2017;88(14):1329-1333. https://doi.org/10.1212/WNL.0000000000003795
Todd N, McDannold N, Borsook D. Targeted manipulation of pain neural networks: The potential of focused ultrasound for treatment of chronic pain. Neurosci Biobehav Rev. 2020;115:238-250. https://doi.org/10.1016/j.neubiorev.2020.06.007
Germann J, Elias GJB, Neudorfer C, et al. Potential optimization of focused ultrasound capsulotomy for obsessive compulsive disorder. Brain. 2021;144(11):3529-3540. https://doi.org/10.1093/brain/awab232
Jung HH, Chang WS, Rachmilevitch I, et al. Different magnetic resonance imaging patterns after transcranial magnetic resonance-guided focused ultrasound of the ventral intermediate nucleus of the thalamus and anterior limb of the internal capsule in patients with essential tremor or obsessive-compulsive disorder. J Neurosurg. 2015;122(1):162-168. https://doi.org/10.3171/2014.8.JNS132603
Medel R, Monteith S, Elias WJ, et al. Magnetic resonance-guided focused ultrasound surgery. Review of current and future applications. Neurosurg. 2012;71(4):755-763. https://doi.org/10.1227/NEU.0b013e3182672ac9
Burgess A, Hynynen K. Noninvasive and Targeted Drug Delivery to the Brain Using Focused Ultrasound. ACS Chem Neurosci. 2013;4(4):519-526. https://doi.org/10.1021/cn300191b
Hynynen K, McDannold N, Vykhodtseva N, Jolesz FA. Noninvasive MR Imaging-guided Focal Opening of the Blood-Brain Barrier in Rabbits. Radiology. 2001;220(3):640-646. https://doi.org/10.1148/radiol.2202001804
Sheikov N, McDannold N, Vykhodtseva N, et al. Cellular mechanisms of the blood-brain barrier opening induced by ultrasound in presence of microbubbles. Ultrasound in medicine & biology. 2004;30:979-989. https://doi.org/10.1016/j.ultrasmedbio.2004.04.010
Kim H, Taghados SJ, Fischer K, et al. Noninvasive transcranial stimulation of rat abducens nerve by focused ultrasound. Ultrasound Med Biol. 2012;38:1568-1575. https://doi.org/10.1016/j.ultrasmedbio.2012.04.023
Lee YF, Lin CC, Cheng JS, Chen GS. High-intensity focused ultrasound attenuates neural responses of sciatic nerves isolated from normal or neuropathic rats. Ultrasound Med Biol. 2015;41:132-142. https://doi.org/10.1016/j.ultrasmedbio.2014.08.014
Krasovitski B, Frenkel V, Shoham S, Kimmel E. Intramembrane cavitation as a unifying mechanism for ultrasound-induced bioeffects. Proc Natl Acad Sci U S A. 2011;108:3258-3263. https://doi.org/10.1073/pnas.1015771108
Bystritsky A, Korb AS. A review of low-intensity transcranial focused ultrasound for clinical applications. Current Behavioral Neuroscience Reports. 2015;2(2):60-66. https://doi.org/10.1007/s40473-015-0039-0
Min BK, Yang PS, Bohlke M, et al. Focused ultrasound modulates the level of cortical neurotransmitters: potential as a new functional brain mapping technique. Int J Imaging Syst Technol. 2011;21:232-240. https://doi.org/10.1002/ima.20284
Burgess A, Dubey S, Yeung S, et al. Alzheimer disease in a mouse model: MR imaging-guided focused ultrasound targeted to the hippocampus opens the blood-brain barrier and improves pathologic abnormalities and behavior. Radiology. 2014;273(3):736-745. https://doi.org/10.1148/radiol.14140245
Kobus T, Vykhodtseva N, Pilatou M, et al. Safety Validation of Repeated Blood-Brain Barrier Disruption Using Focused Ultrasound. Ultrasound Med Biol. 2016;42(2):481-492. https://doi.org/10.1016/j.ultrasmedbio.2015.10.009
Hsu PH, Lin YT, Chung YH, et al. Focused Ultrasound-Induced Blood-Brain Barrier Opening Enhances GSK-3 Inhibitor Delivery for Amyloid-Beta Plaque Reduction. Sci Rep. 2018;8(1):12882. https://doi.org/10.1038/s41598-018-31071-8
Karakatsani ME, Kugelman T, Ji R, et al. Unilateral Focused Ultrasound-Induced Blood-Brain Barrier Opening Reduces Phosphorylated Tau from The rTg4510 Mouse Model. Theranostics. 2019;9(18):5396-5411. https://doi.org/10.7150/thno.28717
Nisbet RM, Van der Jeugd A, Leinenga G, et al. Combined effects of scanning ultrasound and a tau-specific single chain antibody in a tau transgenic mouse model. Brain. 2017;140(5):1220-1230. https://doi.org/10.1093/brain/awx052
Jordão JF, Ayala-Grosso CA, Markham K, et al. Antibodies targeted to the brain with image-guided focused ultrasound reduces amyloid-beta plaque load in the TgCRND8 mouse model of Alzheimer’s disease. PLoS One. 2010;5(5):e10549. https://doi.org/10.1371/journal.pone.0010549
Leinenga G, Götz J. Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer’s disease mouse model. Sci Transl Med. 2015;7(278):278-233. https://doi.org/10.1126/scitranslmed.aaa2512
Shin J, Kong C, Lee J, et al. Focused ultrasound-induced blood-brain barrier opening improves adult hippocampal neurogenesis and cognitive function in a cholinergic degeneration dementia rat model. Alzheimers Res Ther. 2019;11(1):110. https://doi.org/10.1186/s13195-019-0569-x
Alecou T, Giannakou M, Damianou C. Amyloid β Plaque Reduction with Antibodies Crossing the Blood-Brain Barrier, Which Was Opened in 3 Sessions of Focused Ultrasound in a Rabbit Model. J Ultrasound Med. 2017;36(11):2257-2270. https://doi.org/10.1002/jum.14256
O’Reilly MA, Jones RM, Barrett E, et al. Investigation of the Safety of Focused Ultrasound-Induced Blood-Brain Barrier Opening in a Natural Canine Model of Aging. Theranostics. 2017;7(14):3573. https://doi.org/10.1016/S0140-6736(20)31208-3
Eguchi K, Shindo T, Ito K, et al. 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 Sep-Oct;11(5):959-973. https://doi.org/10.1016/j.brs.2018.05.012
Luo K, Wang Y, Chen WS, et al. Treatment Combining Focused Ultrasound with Gastrodin Alleviates Memory Deficit and Neuropathology in an Alzheimer’s Disease-Like Experimental Mouse Model. Neural Plast. 2022;2022:5241449. https://doi.org/10.1155/2022/5241449
Mi X, Du H, Guo X, et al. Asparagine endopeptidase-targeted Ultrasound-responsive Nanobubbles Alleviate Tau Cleavage and Amyloid-β Deposition in an Alzheimer’s Disease Model. Acta Biomater. 2022;1742-7061(22):00030-7. https://doi.org/10.1016/j.actbio.2022.01.023
Poon CT, Shah K, Lin C, et al. Time course of focused ultrasound effects on β-amyloid plaque pathology in the TgCRND8 mouse model of Alzheimer’s disease. Sci Rep. 2018;8(1):14061. https://doi.org/10.1038/s41598-018-32250-3
Lipsman N, Meng Y, Bethune AJ, et al. Blood-brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound. Nat Commun. 2018;9(1):2336. https://doi.org/10.1038/s41467-018-04529-6
Rezai AR, Ranjan M, D’Haese PF, et al. Noninvasive hippocampal blood-brain barrier opening in Alzheimer’s disease with focused ultrasound. Proc Natl Acad Sci U S A. 2020;117(17):9180-9182. https://doi.org/10.1073/pnas.2002571117
D’Haese PF, Ranjan M, Song A, et al. β-Amyloid Plaque Reduction in the Hippocampus After Focused Ultrasound-Induced Blood-Brain Barrier Opening in Alzheimer’s Disease. Front Hum Neurosci. 2020;14:593672. https://doi.org/10.3389/fnhum.2020.593672
Park SH, Baik K, Jeon S, et al. Extensive frontal focused ultrasound mediated blood-brain barrier opening for the treatment of Alzheimer’s disease: a proof-of-concept study. Transl Neurodegener. 2021;10(1):44. https://doi.org/10.1186/s40035-021-00269-8
Keep RF, Jones HC, Drewes LR. Progress in brain barriers and brain fluid research in 2017. Fluids Barriers CNS. 2018;15(1):6. https://doi.org/10.1186/s40035-021-00269-8
Meng Y, MacIntosh BJ, Shirzadi Z, et al. Resting state functional connectivity changes after MR-guided focused ultrasound mediated blood-brain barrier opening in patients with Alzheimer’s disease. Neuroimage. 2019;200:275-280. https://doi.org/10.1016/j.neuroimage.2019.06.060
Jeong H, Im JJ, Park JS, et al. A pilot clinical study of low-intensity transcranial focused ultrasound in Alzheimer’s disease. Ultrasonography. 2021 Oct;40(4):512-519. https://doi.org/10.14366/usg.20138