Paul S. Fishman*
Jonathan M. Fischell- Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, United States
The blood brain barrier (BBB) is an obstacle for the delivery of potential molecular therapies for neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Although there has been a proliferation of potential disease modifying therapies for these progressive conditions, strategies to deliver these large agents remain limited. High intensity MRI guided focused ultrasound has already been FDA approved to lesion brain targets to treat movement disorders, while lower intensity pulsed ultrasound coupled with microbubbles commonly used as contrast agents can create transient safe opening of the BBB. Pre-clinical studies have successfully delivered growth factors, antibodies, genes, viral vectors, and nanoparticles in rodent models of AD and PD. Recent small clinical trials support the safety and feasibility of this strategy in these vulnerable patients. Further study is needed to establish safety as MRI guided BBB opening is used to enhance the delivery of newly developed molecular therapies.
In spite of major gains in the understanding of the biology of neurodegenerative disease such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease, they remain progressively disabling and deadly conditions. Although many agents have provided neuroprotection in cellular and animal models of these conditions, none has resulted in clinically meaningful modification of their progressively worsening natural course. The need for effective disease modifying therapy (DMT) is so dire that agents with likely marginal benefit such as the recently FDA approved aducanumab for AD generate great public interest (1).
Although the factors responsible for the widespread failures of promising agents to translate into clinically effective DMTs are complex, a role for poor brain bioavailability has been suggested (2). This is particularly true for the growing pharmacopeia of molecular therapies including growth factors, enzymes, monoclonal antibodies, and genetic material, all too large to cross the specialized endothelia that compose the blood-brain barrier (BBB). Unfortunately, the intensity of research progress in the development of molecular therapies has greatly outpaced the development of strategies for their delivery to brain.
Contemporary clinical trials of gene therapy for neurodegenerative disease continue to rely on invasive methods such intracerebral infusion (3, 4). The most well-explored strategy to allow large molecules to cross the BBB has been the creation of hybrid molecules that contain a domain the binds to brain endothelial membrane transport receptors such as the transferrin and insulin receptors (5). These “trojan horse” therapeutics have begun to enter clinical trials (6). There has been a resurgence in interest in intra-arterial infusion of hyperosmolar solutions of mannitol to open the BBB, a method initially developed in the 1980's (7, 8).
The newest strategy to enhance delivery of therapeutics from blood to brain is to use focused ultrasound (FUS). The specialized endothelia of the brain have continuous tight junctions that form the BBB, limiting the movement of large molecules from the bloodstream into brain. Studies by Hynynen, McDannold, and colleagues (9–12) initially demonstrated that FUS applied during the circulation of microbubble suspensions (FDA-approved ultrasound contrast agents) can create a transient and safe disruption of the BBB, which can be targeted to a specific brain region using MRI. This allows large therapeutics to enter the brain from the systemic circulation including antibodies, growth factors, nanoparticles, nucleic acids, viral vectors, and even cells (13–19). Using pulsed ultrasound at a much lower intensity than the continuous ultrasound used for brain tissue ablation, the microbubbles undergo oscillations of expansion and contraction that cause transient separation of endothelial tight junctions—the basis for the BBB (20, 21). The procedure can create transient (hours) opening of the BBB, sufficient to allow extravasation of large therapeutics without pathology or entry of blood components (22, 23).
Delivery of large therapeutics across the BBB with any strategy has been limited by the inefficiency of the transfer where accumulation of 1–2% of the total blood injectate in the brain is a true accomplishment (5). Within safe parameters, BBB opening may last only a few hours, and the amount of the therapeutic entering brain is usually much less. Studies of molecular therapies usually find that <0.1% of the injected agent can be detected in the sonicated region of brain after MRgFUS-mediated opening of the BBB (24).
The first application of this strategy was in brain tumor therapy where in preclinical models of brain metastatic breast cancer, FUS-mediated BBB opening substantially improved the efficacy of the antihuman epidermal growth factor 2 monoclonal antibody trastuzumab (24). Clinical trials of FUS opening to enhance chemotherapy of brain tumors are currently in progress (25).
For neurodegenerative diseases, studies using MRI guided FUS (MRgFUS) have enhanced delivery of several potential DMTs including genes in preclinical models of PD. The delivery of glial cell-derived neurotrophic factor (GDNF) and the related factor neurturin from the blood was improved in rodents with the use of this strategy (26, 27). Gene delivery of GDNF has been successful in restoring dopamine metabolism and reversing motor abnormalities in a toxin-induced rat model of PD (28). In an effort to improve the efficiency of delivery (a persistent problem with all blood to brain strategies), the plasmid was preloaded into the microbubbles to enhance its concentration in the region of FUS-mediated BBB opening.
Gene delivery for GDNF has also been successful with enhanced brain distribution using brain penetrant nanoparticles with FUS mediated BBB disruption (D) in the 6-OHDA rodent model of PD (29). Another strategy to improve efficiency of delivery of FUS mediated BBBD has been the use of viral vectors (19, 30). Gene delivery using an adeno associated viral (AAV) vector for GDNF was effective in ameliorating the sub-acute MPTP injection rodent model of PD (31). These studies demonstrate that FUS mediated BBBD can clearly be combined with other delivery methods in the goal of improving the efficiency of brain delivery while still minimizing invasiveness. In a highly novel approach, FUS enhanced the distribution of intranasally delivered BDNF. Although the mechanism of this enhancement is uncertain, this combination successfully improved mice exposed to MPTP (32). Similar mechanism may underlie FUS mediated improvement in distribution of therapeutics after convection-enhanced intracerebral injection, which is the current clinical standard for delivery of protein and gene therapy to the brain (33, 34).
More than 30 years after the initial clinical trials, cell-based therapy has yet to fulfill its promise as a DMT for neurodegenerative disease. As with gene therapy, clinical studies of stem cells for PD still rely on intraparenchymal injection (35, 36). In spite of their large size, rodent studies have demonstrated enhanced delivery of stem cells to brain from the blood, which may involve active mechanism such as chemoattraction and transcytosis across the brain endothelium (37). At this point, however, a beneficial effect of FUS enhanced stem cell delivery has yet to be demonstrated in an animal model of a neurodegenerative disease.
There is also a strong body of evidence from animal studies suggesting the potential benefit of BBBD in AD. These studies explored the possibility that BBBD could be a tool to accelerate the clearance of beta-amyloid from the brain—a major goal of many current AD experimental therapeutics. Studies in mouse models of AD have demonstrated both reduction in brain amyloid burden and behavioral improvement using BBBD coupled with either infused or endogenous anti-amyloid antibodies (18, 38). This reduction in amyloid burden and improved behavior occurred without evidence of brain hemorrhage, a known risk of FUS as well as a clear concern when considering the coexistence of amyloid angiopathy in AD with its significant risk of brain hemorrhage (39). One of the AD/amyloid animal studies demonstrated that moving the target of sonication through the brain (scanning FUS) could be a potential useful strategy for treatment of a large brain volume (40).
As with most antibodies, relatively little of an anti-amyloid antibody enters the brain from an IV injection [0.1% (41)]. However, these antibodies appear to have the capacity to accumulate in the AD brain, likely due to binding to brain amyloid (42). The mechanism by which anti-amyloid antibodies in the blood reduce brain amyloid burden without significant entry into brain remains controversial and how FUS potentiates amyloid clearance is under active investigation (43, 44). There is also concern that compromise of the BBB may also interfere with normal amyloid clearance from the brain (45).
FUS mediated BBB opening also appears to stimulate neurogenesis in the treated region, although once again the mechanism involved is uncertain (46, 47).
In spite of these promising pre-clinical rodent studies, the path to clinical trials of BBBD for neurodegenerative disease is not straightforward. All potential therapeutics utilized in the animal studies are experimental, without full FDA approval. A trial that combines a first of its kind study of an experimental delivery method such as FUS mediated BBBD with an experimental agent such as gene therapy would pose unknown risks to this fragile patient population that may be additive. This is particularly relevant to the combined use of BBBD for delivery of an anti-amyloid antibody where there is overlap in potential adverse effects and pathology. FUS mediated BBBD carries with it a risk of excessive disruption of the BBB resulting in brain edema and hemorrhage although neither pathology was observed in animal studies with transgenic AD mice or aged dogs with amyloid deposition (48). An increase in multiple inflammatory markers has been described in other animal studies of FUS mediated BBBD (49). Both brain edema and hemorrhage are also risk of treatment with monoclonal antibodies against amyloid for AD (50).
The possibility of additive and unknown risks with the combination of an experimental agent and an experimental delivery method influenced the design of the first clinical trial of FUS mediated BBBD in patients with AD. Supported by the pre-clinical studies, patient with mild to moderate AD underwent BBBD alone, without infusion of an anti-amyloid antibody (51). A frontal cortex location was chosen as the sonication target, reflecting the emphasis on safety in this first of kind study. Although a hippocampal target could be viewed as more clinically important, its deep location was felt to pose a greater risk if significant edema or bleeding were to occur. Patients who tolerated a relatively small volume of BBBD had the procedure repeated later targeting a larger volume. This study supported both the feasibility of opening the BBBD in AD patients (using gadolinium extravasation as an outcome measure) as well as its safety. No significant change in amyloid signal on PET scans or cognitive change was detected, although the study was not powered to assess these efficacy outcomes. There was no significant edema or bleeding among the five treated patients, although transient evidence of possible micro-hemorrhage was observed.
A subsequent study of six patients with AD targeting the hippocampus also supported the safety of FUS mediated BBBD (52). This group of patients also showed a modest reduction of amyloid related signal on 18 F-Florbetaben PET the after three rounds of BBBD over 6 months (53).
It should be noted that this is one of several setting where FUS mediated BBBD will need to be performed on a repeated basis. This will also increase an aspect of brain FUS that reduces patient satisfaction, that of complete shaving of the head, which contemporary neurosurgical procedures tend to avoid. With the recent FDA approval of aducanumab (Aduhelm), it is likely that this agent will be combined with FUS mediated BBBD in the near future. A recent study in an AD transgenic mouse has already assessed the combination of a murine aducanumab analog and BBBD using scanning FUS (54). As expected, FUS substantially increased the distribution and amount of this anti-amyloid antibody in the brain. It is encouraging that a potential safety outcome—brain microhemorrhages—were not increased in any of the treatment groups including combination treatment. Although the effect on clearance of amyloid from the brain varied with brain region (increased clearance with combination treatment of frontal cortex but not in the hippocampus), there was substantial improvement in performance on a spatial memory tasks only with combination treatment. Although the hypothesis is that this combined approach will be more effective than either modality alone for both removal of cerebral amyloid and clinical improvement, safety will remain the primary outcome measure in the initial studies.
A similar approach has been utilized in patients with PD dementia (55). Although PD has predominantly intracellular accumulation of pathologic forms of alpha synuclein, PD dementia is strongly associated with a combination of alpha synuclein and amyloid deposition (56). This recent study of five patients supports the safety of multiple repeated rounds of BBBD of a target region at the parieto-occipito-temporal junction. Although mild improvement in cognition was observed, no significant change in either amyloid or fluorodeoxy glucose by PET scan was observed.
The strategy of combining FUS mediated BBBD with an approved therapeutic is currently underway with a potential DMT for PD. There is a strong association between Gaucher's disease, a lysosomal storage disease caused by mutant forms of the enzyme glucocerebrosidase (GCase) with PD (57). Studies of the interaction of this enzyme with alpha synuclein have also supported GCase as a possible DMT for PD (58). A recombinant form of normal GCase has been an FDA approved therapy for Gaucher's disease for many years (59). As with all forms of enzyme replacement therapy, large molecular size prevents crossing the BBB with limited benefit for CNS forms of diseases associated with detective endogenous enzyme such as Gaucher's. A clinical trial where PD patients are infused intravenously with GCase at the same time as BBBD targeted to the basal ganglia is currently in progress (ClinicalTrials.gov identifier NCT04370665).
The safety of BBBD even in patients where a region with symptomatic neuronal dysfunction is directly targeted is supported by the first study of FUS mediated BBBD in patients with ALS (60). The four volunteers showed no worsening of their motor function after successful BBBD targeted to their motor cortex. The goal of this study as preparation to deliver molecular therapeutics to corticospinal neuronal cell bodies reflects a contemporary review of ALS which emphasizes both the physiologic importance of these “upper motorneurons” in motor symptoms as well as the “dying forward” nature of its pathogenesis that likely begins in the cell soma (61, 62).
These studies illustrate the potential of FUS mediated BBBD to enhance potential DMT for neurodegenerative disease. The initial clinical experience suggests that pulsed FUS coupled with microbubble infusion can result in safe, transient localized opening of the BBBD in patients with AD, PD, and ALS. Pre-clinical studies suggest that this form of BBBD may amplify the efficacy of circulating endogenous and exogenous molecules that are too large to cross the normal BBBD. As the safety of FUS mediated BBBD becomes more established, the opportunities for utilizing it to delivery experimental therapies show as gene therapies will develop. The combination of effective molecular agents and a safe strategy to enhance their delivery to brain such as FUS mediated BBB opening could accelerate the development of clinical useful disease modifying therapies for the million of patients suffering from progressive neurodegenerative diseases.
Author Contributions
PF had primary responsibility for the review of the studies cited and writing of the paper. JF verified the accuracy of the representation of the cited literature. Both authors contributed to the article and approved the submitted version.
Conflict of Interest
PF has received funding from Insightec which has funded some of the clinical studies cited.
The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The handling Editor declared a past co-authorship with one of the authors, PF.
Publisher's Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. de la Torre JC, Gonzalez-Lima F. The FDA approves aducanumab for Alzheimer's disease, raising important scientific questions. J Alzheimers Dis. (2021) 2021:210736. doi: 10.3233/JAD-210736
2. Kimura S, Harashima H. Current status and challenges associated with CNS-targeted gene delivery across the BBB. Pharmaceutics. (2020) 12:1216. doi: 10.3390/pharmaceutics12121216
3. Hitti FL, Yang AI, Gonzalez-Alegre P, Baltuch GH. Human gene therapy approaches for the treatment of Parkinson's disease: an overview of current andcompleted clinical trials. Parkinsonism Relat Disord. (2019) 66:16–24. doi: 10.1016/j.parkreldis.2019.07.018
4. Olanow CW, Bartus RT, Baumann TL, Factor S, Boulis N, Stacy M, et al. Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: a double-blind, randomized, controlled trial. Ann Neurol. (2015) 78:248–57. doi: 10.1002/ana.24436
5. Pardridge WM, Boado RJ. Reengineering biopharmaceuticals for targeted delivery across the blood-brain barrier. Methods Enzymol. (2012) 503:269–92. doi: 10.1016/B978-0-12-396962-0.00011-2
6. Giugliani R, Giugliani L, de Oliveira Poswar F, Donis KC, Corte AD, Schmidt M, et al. Neurocognitive and somatic stabilization in pediatric patients with severe Mucopolysaccharidosis Type I after 52 weeks of intravenous brain-penetrating insulin receptor antibody-iduronidase fusion protein (valanafusp alpha): an open label phase 1–2 trial. Orphanet J Rare Dis. (2018) 13:110. doi: 10.1186/s13023-018-0849-8
7. Gonzales-Portillo GS, Sanberg PR, Franzblau M, Gonzales-Portillo C, Diamandis T, Staples M, et al. Mannitol-enhanced delivery of stem cells and their growth factors across the Blood-Brain barrier. Cell Transplant. (2014) 23:531–9. doi: 10.3727/096368914X678337
8. Doolittle ND, Muldoon LL, Culp AY, Neuwelt EA. Delivery of chemotherapeutics across the blood–brain barrier: challenges and advances. Adv Pharmacol. (2014) 71:203–43. doi: 10.1016/bs.apha.2014.06.002
9. Sheikov N, McDannold N, Vykhodtseva N, Jolesz F, Hynynen K. Cellular mechanisms of the blood-brain barrier opening induced by ultrasound in presence of microbubbles. Ultrasound Med Biol. (2004) 30:979–89. doi: 10.1016/j.ultrasmedbio.2004.04.010
10. McDannold N, Vykhodtseva N, Hynynen K. Use of ultrasound pulses combined with definity for targeted blood-brain barrier disruption: a feasibility study. Ultrasound Med Biol. (2007) 33:584–90. doi: 10.1016/j.ultrasmedbio.2006.10.004
11. Hynynen K. Focused ultrasound for blood–brain disruption and delivery of therapeutic molecules into the brain. Expert Opin Drug Deliv. (2007) 4:27–35. doi: 10.1517/17425247.4.1.27
12. Hynynen K. Macromolecular delivery across the blood–brain barrier. Methods Mol Biol. (2009) 480:175–85. doi: 10.1007/978-1-59745-429-2_13
13. Huang Q, Deng J, Wang F, Chen S, Liu Y, Wang Y, et al. Targeted gene delivery to the mouse brain by MRI-guided focused ultrasound-induced blood–brain barrier disruption. Exp Neurol. (2012) 233:350–6. doi: 10.1016/j.expneurol.2011.10.027
14. Fan CH, Ting C, Lin H, Wang C, Liu H, Yen T, et al. SPIO-conjugated, doxorubicin-loaded microbubbles for concurrent MRI and focused-ultrasound enhanced brain-tumor drug delivery. Biomaterials. (2013) 34:3706–15. doi: 10.1016/j.biomaterials.2013.01.099
15. Burgess A, Ayala-Grosso CA, Ganguly M, Jordão JF, Aubert I, Hynynen K. Targeted delivery of neural stem cells to the brain using MRI-guided focused ultrasound to disrupt the blood-brain barrier. PLoS ONE. (2011) 6:e27877. doi: 10.1371/journal.pone.0027877
16. Burgess A, Huang Y, Querbes W, Sah DW, Hynynen K. Focused ultrasound for targeted delivery of siRNA and efficient knockdown of htt expression. J Control Release. (2012) 163:125–9. doi: 10.1016/j.jconrel.2012.08.012
17. Shen WB, Anastasiadis P, Nguyen B, Yarnell D, Yarowsky PJ, Frenkel V, et al. Magnetic enhancement of stem cell-targeted delivery into the brain following MR-guided focused ultrasound for opening the blood-brain barrier. Cell Transplant. (2017) 26:1235–46. doi: 10.1177/0963689717715824
18. Jordão JF, Ayala-Grosso CA, Markham K, Huang Y, Chopra R, McLaurin J, 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:e10549. doi: 10.1371/journal.pone.0010549
19. Thevenot E, Jordao JF, O'Reilly MA, Markham K, Weng YQ, Foust KD, et al. Targeted delivery of self-complementary adeno-associated virus serotype 9 to thebrain, using magnetic resonance imaging-guided focused ultrasound. Hum Gene Ther. (2012) 23:1144–55. doi: 10.1089/hum.2012.013
20. Konofagou EE, Tung YS, Choi J, Deffieux T, Baseri B, Vlachos F. Ultrasound- induced blood-brain barrier opening. Curr Pharm Biotechnol. (2012) 13:1332–45. doi: 10.2174/138920112800624364
21. Lin CY, Hsieh HY, Chen CM, Wu SR, Tsai CH, Huang CY, et al. Non-invasive, neuron-specific gene therapy by focused ultrasound-induced blood-brain barrier opening in Parkinson's disease mouse model. J Control Release. (2016) 235:72–81. doi: 10.1016/j.jconrel.2016.05.052
22. Kobus T, Vykhodtseva N, Pilatou M, Zhang Y, McDannold N. Safety validation of repeated Blood–Brain barrier disruption using focused ultrasound. Ultrasound Med Biol. (2016) 42:481–92. doi: 10.1016/j.ultrasmedbio.2015.10.009
23. Jolesz FA, McDannold NJ. Magnetic resonance–guided focused ultrasound: a new technology for clinical neurosciences. Neurol Clin. (2014) 32:253–69. doi: 10.1016/j.ncl.2013.07.008
24. Kinoshita M, McDannold N, Jolesz FA, Hynynen K. Noninvasive localized delivery of herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption. Proc Natl Acad Sci USA. (2006) 103:11719–23. doi: 10.1073/pnas.0604318103
25. Mainprize T, Lipsman N, Huang Y, Meng Y, Bethune A, Ironside S, et al. Blood-brain barrier openingin primary brain tumors with non-invasive MR-guided focused ultrasound: a clinical safety and feasibility study. Sci Rep. (2019) 9:321. doi: 10.1038/s41598-018-36340-0
26. Wang F, Shi Y, Lu L, Liu L, Cai Y, Zheng H, et al. Targeted delivery of GDNF through the blood–brain barrier by MRI-guided focused ultrasound. PLoS ONE. (2012) 7:e52925. doi: 10.1371/journal.pone.0052925
27. Samiotaki G, Acosta C, Wang S, Konofagou EE. Enhanced delivery and bioactivity of the neurturin neurotrophic factor through focused ultrasound- mediated blood–brain barrier opening in vivo. J Cereb Blood Flow Metab. (2015) 35:611–22. doi: 10.1038/jcbfm.2014.236
28. Fan CH, Ting CY, Lin CY, Chan HL, Chang YC, Chen YY, et al. Noninvasive, targeted, and non-viral ultrasound-mediated GDNF-plasmid delivery for treatment of Parkinson's disease. Sci Rep. (2016) 6:19579. doi: 10.1038/srep19579
29. Mead BP, Kim N, Miller GW, Hodges D, Mastorakos P, Klibanov AL, et al. Novel focused ultrasound gene therapy approach noninvasively restores dopaminergic neuron function in a rat Parkinson's disease model. Nano Lett. (2017) 17:3533–42. doi: 10.1021/acs.nanolett.7b00616
30. Alonso A, Reinz E, Leuchs B, Kleinschmidt J, Fatar M, Geers B, et al. Focal delivery of AAV2/1-transgenes into the rat brain by localized ultrasound-induced BBB opening. Mol Ther. (2013) 2:e73. doi: 10.1038/mtna.2012.64
31. Karakatsani ME, Wang S, Samiotaki G, Kugelman T, Olumolade OO, Acosta C, et al. Amelioration of the nigrostriatal pathway facilitated by ultrasound-mediatedneurotrophic delivery in early Parkinson's disease. J Control Release. (2019) 303:289–301. doi: 10.1016/j.jconrel.2019.03.030
32. Ji R, Smith M, Niimi Y, Karakatsani ME, Murillo MF, Jackson-Lewis V, et al. Focused ultrasound enhanced intranasal delivery of brain derived neurotrophic factor produces neurorestorative effects in a Parkinson's disease mouse model. Sci Rep. (2019) 9:19402. doi: 10.1038/s41598-019-55294-5
33. Fiandaca MS, Lonser RR, Elder JB, Zabek M, Bankiewicz KS. Advancing gene therapies, methods, and technologies for Parkinson's Disease and other neurological disorders. Neurol Neurochir Pol. (2020) 54:220–31. doi: 10.5603/PJNNS.a2020.0046
34. Hersh DS, Anastasiadis P, Mohammadabadi A, Nguyen BA, Guo S, Winkles JA, et al. MR-guided transcranial focused ultrasound safely enhances interstitial dispersion of large polymeric nanoparticles in the living brain. PLoS ONE. (2018) 13:e0192240. doi: 10.1371/journal.pone.0192240
35. Spencer DD, Robbins RJ, Naftolin F, Marek KL, Vollmer T, Leranth C, et al. Unilateral transplantation of human fetal mesencephalic tissue into the caudate nucleus of patients with Parkinson's disease. N Engl J Med. (1992) 327:1541–8. doi: 10.1056/NEJM199211263272201
36. Schweitzer JS, Song B, Herrington TM, Park TY, Lee N, Ko S, et al. Personalized iPSC-derived dopamine progenitor cells for Parkinson's disease. N Engl J Med. (2020) 382:1926–32. doi: 10.1056/NEJMoa1915872
37. Ahmed N, Gandhi D, Melhem ER, Frenkel V. MRI guided focused ultrasound-mediated delivery of therapeutic cells to the brain: a review of the state-of-the-art methodology and future applications. Front Neurol. (2021) 12:669449. doi: 10.3389/fneur.2021.669449
38. Jordão JF, Thévenot E, Markham-Coultes K, Scarcelli T, Weng YQ, Xhima 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. doi: 10.1016/j.expneurol.2013.05.008
39. Jäkel L, De Kort AM, Klijn CJM, Schreuder FHBM, Verbeek MM. Prevalence of cerebral amyloid angiopathy: a systematic review and meta-analysis. Alzheimers Dement. (2021) 2021:alz.12366. doi: 10.1002/alz.12366
40. Leinenga G, Götz J. Safety and efficacy of scanning ultrasound treatment of aged APP23 mice. Front Neurosci. (2018) 12:55. doi: 10.3389/fnins.2018.00055
41. Banks WA, Terrell B, Farr SA, Robinson SM, Nonaka N, Morley JE. Passage of amyloid beta protein antibody across the blood-brain barrier in a mouse model of Alzheimer's disease. Peptides. (2002) 23:2223–6. doi: 10.1016/S0196-9781(02)00261-9
42. Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature. (2016) 537:50–6. doi: 10.1038/nature19323
43. Levites Y, Smithson LA, Price RW, Dakin RS, Yuan B, Sierks MR, et al. Insights into the mechanisms of action of anti-Abeta antibodies in Alzheimer's disease mouse models. FASEB J. (2006) 20:2576–8. doi: 10.1096/fj.06-6463fje
44. Lee Y, Choi Y, Park EJ, Kwon S, Kim H, Lee JY, et al. Improvement of glymphatic-lymphatic drainage of beta-amyloid by focused ultrasound in Alzheimer's disease model. Sci Rep. (2020) 10:16144. doi: 10.1038/s41598-020-73151-8
45. Cockerill I, Oliver JA, Xu H, Fu BM, Zhu D. Blood-brain barrier integrity and clearance of amyloid-β from the BBB. Adv Exp Med Biol. (2018) 1097:261–78. doi: 10.1007/978-3-319-96445-4_14
46. Burgess A, Dubey S, Yeung S, Hough O, Eterman N, Aubert I, 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) 273:736–45. doi: 10.1148/radiol.14140245
47. Dubey S, Heinen S, Krantic S, McLaurin J, Branch DR, Hynynen K, et al. Clinically approved IVIg delivered to the hippocampus with focused ultrasound promotes neurogenesis in a model of Alzheimer's disease. Proc Natl Acad Sci USA. (2020) 117:32691–700. doi: 10.1073/pnas.1908658117
48. O'Reilly MA, Jones RM, Barrett E, Schwab A, Head E, Hynynen K. Investigation of the safety of focused ultrasound-induced blood-brain barrier opening in a natural canine model of aging. Theranostics. (2017) 7:3573–84. doi: 10.7150/thno.20621
49. Kovacs ZI, Kim S, Jikaria N, Qureshi F, Milo B, Lewis BK, et al. Disrupting the blood-brain barrier by focused ultrasound induces sterile inflammation. Proc Natl Acad Sci USA. (2017) 114:E75–84. doi: 10.1073/pnas.1614777114
50. Avgerinos KI, Ferrucci L, Kapogiannis D. Effects of monoclonal antibodies against amyloid-β on clinical and biomarker outcomes and adverse event risks: a systematic review and meta-analysis of phase III RCTs in Alzheimer's disease. Ageing Res Rev. (2021) 68:101339. doi: 10.1016/j.arr.2021.101339
51. Lipsman N, Meng Y, Bethune AJ, Huang Y, Lam B, Masellis M, et al. Blood-brain barrier opening in Alzheimer's disease using MR-guided focused ultrasound. Nat Commun. (2018) 9:2336. doi: 10.1038/s41467-018-04529-6
52. Rezai AR, Ranjan M, D'Haese PF, Haut MW, Carpenter J, Najib U, et al. Noninvasive hippocampal blood-brain barrier opening in Alzheimer's disease with focused ultrasound. Proc Natl Acad Sci USA. (2020) 117:9180–2. doi: 10.1073/pnas.2002571117
53. D'Haese PF, Ranjan M, Song A, Haut MW, Carpenter J, Dieb G, 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. doi: 10.3389/fnhum.2020.593672
54. Leinenga G, Koh WK, Götz J. A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease. Alzheimers Res Ther. (2021) 13:76. doi: 10.1186/s13195-021-00809-4
55. Gasca-Salas C, Fernández-Rodríguez B, Pineda-Pardo JA, Rodríguez-Rojas R, Obeso I, Hernández-Fernández F, et al. Blood-brain barrier opening with focused ultrasound in Parkinson's disease dementia. Nat Commun. (2021) 12:779. doi: 10.1038/s41467-021-21022-9
56. Irwin DJ, Lee VM, Trojanowski JQ. Parkinson's disease dementia: convergence of α-synuclein, tau and amyloid-β pathologies. Nat Rev Neurosci. (2013) 14:626–36. doi: 10.1038/nrn3549
57. Riboldi GM, Di Fonzo AB. GBA, Gaucher disease, and Parkinson's disease: from genetic to clinic to new therapeutic approaches. Cells. (2019) 8:364. doi: 10.3390/cells8040364
58. Do J, McKinney C, Sharma P, Sidransky E. Glucocerebrosidase and its relevance to Parkinson disease. Mol Neurodegener. (2019) 14:36. doi: 10.1186/s13024-019-0336-2
59. Pastores GM, Weinreb NJ, Aerts H, Andria G, Cox TM, Giralt M, et al. Therapeutic goals in the treatment of Gaucher disease. Semin Hematol. (2004) 41(4 Suppl.5):4–14. doi: 10.1053/j.seminhematol.2004.07.009
60. Abrahao A, Meng Y, Llinas M, Huang Y, Hamani C, Mainprize T, et al. First-in-human trial of blood-brain barrier opening in amyotrophic lateral sclerosis using MR-guided focused ultrasound. Nat Commun. (2019) 10:4373. doi: 10.1038/s41467-019-12426-9
61. Lemon RN. The cortical “Upper Motoneuron” in health and disease. Brain Sci. (2021) 11:619. doi: 10.3390/brainsci11050619
Keywords: FUS, blood-brain barrier, Alzheimer's disease, Parkinson's disease, focused ultrasound (MRgFUS)
Citation: Fishman PS and Fischell JM (2021) Focused Ultrasound Mediated Opening of the Blood-Brain Barrier for Neurodegenerative Diseases. Front. Neurol. 12:749047. doi: 10.3389/fneur.2021.749047
Received: 28 July 2021; Accepted: 27 September 2021;
Published: 04 November 2021.
Edited by:
Vibhor Krishna, The Ohio State University, United StatesReviewed by:
Fedor Panov, Mount Sinai Health System, United StatesBhavya Shah, University of Texas Southwestern Medical Center, United States
Copyright © 2021 Fishman and Fischell. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Paul S. Fishman, cGZpc2htYW4mI3gwMDA0MDtzb20udW1hcnlsYW5kLmVkdQ==