Extensive frontal focused ultrasound mediated blood–brain barrier opening for the treatment of Alzheimer’s disease: a proof-of-concept study

Park, So Hee; Baik, Kyoungwon; Jeon, Seun; Chang, Won Seok; Ye, Byoung Seok; Chang, Jin Woo

doi:10.1186/s40035-021-00269-8

Cited by 58 publications

(61 citation statements)

References 38 publications

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“…MRgFUS combines transcranial acoustic energy and intravenous microbubbles to disrupt the tight junctions of the targeted capillaries, allowing large therapeutics such as antibodies to gain access to the human human brain (Meng et al, 2021 ). Also, reversible MRgFUS-induced BBB permeability was safely performed in patients with Alzheimer's disease (Lipsman et al, 2018 ; Rezai et al, 2020 ; Park et al, 2021 ), another neurodegenerative condition with chronic BCNSB leakage (Zipser et al, 2007 ).…”

Section: Discussionmentioning

confidence: 99%

Breached Barriers: A Scoping Review of Blood-Central Nervous System Barrier Pathology in Amyotrophic Lateral Sclerosis

Mirian

Moszczynski

Soleimani

et al. 2022

Front. Cell. Neurosci.

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IntroductionRecent studies have implicated changes in the blood-central nervous system barriers (BCNSB) in amyotrophic lateral sclerosis (ALS). The objective of this scoping review is to synthesize the current evidence for BCNSB structure and functional abnormalities in ALS studies and propose how BCNSB pathology may impact therapeutic development.MethodsA literature search was conducted using Ovid Medline, EMBASE, and Web of Science, from inception to November 2021 and limited to entries in English language. Simplified search strategy included the terms ALS/motor neuron disease and [BCNSB or blood-brain barrier (BBB) or blood-spinal cord barrier (BSCB)]. Henceforth, BCNSB is used as a term that is inclusive of the BBB and BSCB. Four independent reviewers conducted a title and abstract screening, hand-searched the reference lists of review papers, and performed a full text review of eligible studies. Included studies were original peer-reviewed full text publications, evaluating the structure and function of the BCNSB in preclinical models of ALS, clinical ALS, or postmortem human ALS tissue. There was no restriction on study design. The four reviewers independently extracted the data.ResultsThe search retrieved 2,221 non-duplicated articles and 48 original studies were included in the synthesis. There was evidence that the integrity of the BCNSB is disrupted throughout the course of the disease in rodent models, beginning prior to symptom onset and detectable neurodegeneration. Increased permeability, pharmacoresistance with upregulated efflux transporters, and morphological changes in the supporting cells of the BCNSB, including pericytes, astrocytes, and endothelial cells were observed in animal models. BCNSB abnormalities were also demonstrated in postmortem studies of ALS patients. Therapeutic interventions targeting BCNSB dysfunction were associated with improved motor neuron survival in animal models of ALS.ConclusionBCNSB structural and functional abnormalities are likely implicated in ALS pathophysiology and may occur upstream to neurodegeneration. Promising therapeutic strategies targeting BCNSB dysfunction have been tested in animals and can be translated into ALS clinical trials.

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Section: Discussionmentioning

confidence: 99%

Breached Barriers: A Scoping Review of Blood-Central Nervous System Barrier Pathology in Amyotrophic Lateral Sclerosis

Mirian

Moszczynski

Soleimani

et al. 2022

Front. Cell. Neurosci.

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“…In their study, LI tFUS targeting the hippocampus has a beneficial impact on cerebral glucose metabolism and memory and improves cognitive function. Thus, a large body of preclinical and clinical evidence suggests that the blood–brain barrier (BBB) opening by FUS can be done safely [ 54 , 55 ]. However, potential risks should be noted, including microbleeds, cellular vacuolation, ischemia due to vasoconstriction, cerebral edema, and direct cellular injury from physical forces, even at the typical low sound pressure [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of transcranial ultrasound stimulation pulsed at 40 Hz on Aβ plaques and brain rhythms in 5×FAD mice

Park

Hoang

Nguyen

et al. 2021

Transl Neurodegener

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Background Alzheimer’s disease (AD) is the most common cause of dementia, and is characterized by amyloid-β (Aβ) plaques and tauopathy. Reducing Aβ has been considered a major AD treatment strategy in pharmacological and non-pharmacological approaches. Impairment of gamma oscillations, which play an important role in perception and cognitive function, has been shown in mouse AD models and human patients. Recently, the therapeutic effect of gamma entrainment in AD mouse models has been reported. Given that ultrasound is an emerging neuromodulation modality, we investigated the effect of ultrasound stimulation pulsed at gamma frequency (40 Hz) in an AD mouse model. Methods We implanted electroencephalogram (EEG) electrodes and a piezo-ceramic disc ultrasound transducer on the skull surface of 6-month-old 5×FAD and wild-type control mice (n = 12 and 6, respectively). Six 5×FAD mice were treated with two-hour ultrasound stimulation at 40 Hz daily for two weeks, and the other six mice received sham treatment. Soluble and insoluble Aβ levels in the brain were measured by enzyme-linked immunosorbent assay. Spontaneous EEG gamma power was computed by wavelet analysis, and the brain connectivity was examined with phase-locking value and cross-frequency phase-amplitude coupling. Results We found that the total Aβ42 levels, especially insoluble Aβ42, in the treatment group decreased in pre- and infra-limbic cortex (PIL) compared to that of the sham treatment group. A reduction in the number of Aβ plaques was also observed in the hippocampus. There was no increase in microbleeding in the transcranial ultrasound stimulation (tUS) group. In addition, the length and number of microglial processes decreased in PIL and hippocampus. Encelphalographic spontaneous gamma power was increased, and cross-frequency coupling was normalized, implying functional improvement after tUS stimulation. Conclusion These results suggest that the transcranial ultrasound-based gamma-band entrainment technique can be an effective therapy for AD by reducing the Aβ load and improving brain connectivity.

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“…For example, discrete or multiple foci enabled restricted or broad whole-hemisphere gene transfer and drug delivery in rodents ( 168 , 263 , 264 ). In humans, although the technology is still in clinical trials, brain volumes from 63 mm 3 to 25 cm 3 have been safely targeted with MRIgFUS for increased BBB permeability ( 265 – 269 ).…”

Section: Non-invasive Drug Delivery To Brainmentioning

confidence: 99%

Alpha-Synuclein Targeting Therapeutics for Parkinson's Disease and Related Synucleinopathies

et al. 2022

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α-Synuclein (asyn) is a key pathogenetic factor in a group of neurodegenerative diseases generically known as synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Although the initial triggers of pathology and progression are unclear, multiple lines of evidence support therapeutic targeting of asyn in order to limit its prion-like misfolding. Here, we review recent pre-clinical and clinical work that offers promising treatment strategies to sequester, degrade, or silence asyn expression as a means to reduce the levels of seed or substrate. These diverse approaches include removal of aggregated asyn with passive or active immunization or by expression of vectorized antibodies, modulating kinetics of misfolding with small molecule anti-aggregants, lowering asyn gene expression by antisense oligonucleotides or inhibitory RNA, and pharmacological activation of asyn degradation pathways. We also discuss recent technological advances in combining low intensity focused ultrasound with intravenous microbubbles to transiently increase blood-brain barrier permeability for improved brain delivery and target engagement of these large molecule anti-asyn biologics.

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Extensive frontal focused ultrasound mediated blood–brain barrier opening for the treatment of Alzheimer’s disease: a proof-of-concept study

Cited by 58 publications

References 38 publications

Breached Barriers: A Scoping Review of Blood-Central Nervous System Barrier Pathology in Amyotrophic Lateral Sclerosis

Breached Barriers: A Scoping Review of Blood-Central Nervous System Barrier Pathology in Amyotrophic Lateral Sclerosis

Effects of transcranial ultrasound stimulation pulsed at 40 Hz on Aβ plaques and brain rhythms in 5×FAD mice

Alpha-Synuclein Targeting Therapeutics for Parkinson's Disease and Related Synucleinopathies

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