Blood–brain barrier opening with focused ultrasound in experimental models of Parkinson's disease

Karakatsani, Maria Eleni; Blesa, Javier; Konofagou, Elisa E.

doi:10.1002/mds.27804

Cited by 46 publications

(39 citation statements)

References 86 publications

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“…A more controlled and less invasive way to disrupt the endothelial tight junctions of the BBB is with FUS . Early attempts in rats suggested that high‐intensity FUS can be adjusted to induce transient thermal BBB disruption without producing a lesion .…”

Section: Bbb Opening To Halt Nigrostriatal Neurodegenerationmentioning

confidence: 99%

“…Soon after this, transient BBB opening was safely achieved by low‐intensity FUS combined with an ultrasound contrast agent (microbubbles) in rabbits, rodents, and primates . The potential of FUS BBB opening for targeted delivery of therapeutic agents, chemotherapy, immunotherapy, gene therapy, viral vectors, neural stem cells, and others is being tested extensively in animal models …”

Section: Bbb Opening To Halt Nigrostriatal Neurodegenerationmentioning

confidence: 99%

“…A more controlled and less invasive way to disrupt the endothelial tight junctions of the BBB is with FUS. 21 Early attempts in rats suggested that high-intensity FUS can be adjusted to induce transient thermal BBB disruption without producing a lesion. 130 Soon after this, transient BBB opening was safely achieved by lowintensity FUS combined with an ultrasound contrast agent (microbubbles) in rabbits, 131,132 rodents, 133 and primates.…”

Section: Bbb Opening To Halt Nigrostriatal Neurodegenerationmentioning

confidence: 99%

“…Thus, MRI‐guided FUS delivered at high intensity produces a focal increase of temperature that can be used for thermal ablation of the targeted brain tissue . On the other hand, MRI‐guided FUS delivered at low intensity combined with ultrasound contrast agents (ie, microbubbles) produces focally controlled mechanical stresses on the capillary walls that can temporarily open the blood–brain barrier (BBB), allowing for targeted delivery of therapeutic agents that would not otherwise move across the BBB in therapeutic quantity …”

mentioning

confidence: 99%

“…18 On the other hand, MRIguided FUS delivered at low intensity combined with ultrasound contrast agents (ie, microbubbles) produces focally controlled mechanical stresses on the capillary walls that can temporarily open the blood-brain barrier (BBB), allowing for targeted delivery of therapeutic agents that would not otherwise move across the BBB in therapeutic quantity. [19][20][21] In the field of movement disorders, MRI-guided FUS ablation have already bridged the gap from the laboratory to the clinic. Specifically: (1) FUS thalamotomy is effective and US Food and Drug Administration approved for essential and parkinsonian tremor [22][23][24] ; (2) FUS pallidotomy has shown preliminary efficacy for treating dyskinesias and motor fluctuations in advanced PD 25 and is being tested with randomized, controlled trials in larger samples (ClinicalTrials.gov: NCT03319485, NCT02347254); (3) FUS subthalamotomy showed promising clinical outcomes for cardinal PD features in a recent pilot study, 26 and its efficacy is currently under scrutiny in a sham-controlled trial (NCT03454425).…”

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Focused ultrasound in Parkinson's disease: A twofold path toward disease modification

et al. 2019

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A major unmet need in Parkinson's disease (PD) is to slow the inexorable progression of neurodegeneration. Clinical trials that evaluated promising pharmacological strategies have repeatedly failed. Nonetheless, the advent of focused ultrasound provides new opportunities toward the goal of developing a safe and effective disease‐modifying therapy for PD. Here we discuss the rationale, possible avenues, and challenges along this path, exploiting the potential of focused ultrasound for (1) performing focal thermal lesions to restore the basic basal ganglia abnormalities associated with dopamine depletion, and (2) transiently opening the blood–brain barrier for targeted delivery of therapeutic agents. First, the classic idea of excitotoxicity mediated by hyperactivity of the subthalamic nucleus suggests that focused ultrasound subthalamotomy may offer a clinically viable disease‐modifying therapy in very‐early PD. Second, the concept of retrograde nigrostriatal neurodegeneration, supported by our recent cortical pathogenic theory of PD, points toward the putamen as a principal site for focused ultrasound blood–brain barrier opening and targeted drug delivery. In principle, both therapeutic strategies—subthalamotomy and putaminal blood–brain barrier opening—could eventually be applied in the same patient. Clinical application is still a long road ahead; nevertheless, focused ultrasound may open a twofold path toward disease modification in PD. © 2019 International Parkinson and Movement Disorder Society

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Section: Bbb Opening To Halt Nigrostriatal Neurodegenerationmentioning

confidence: 99%

Section: Bbb Opening To Halt Nigrostriatal Neurodegenerationmentioning

confidence: 99%

Section: Bbb Opening To Halt Nigrostriatal Neurodegenerationmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Focused ultrasound in Parkinson's disease: A twofold path toward disease modification

et al. 2019

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Neuronal vulnerability in Parkinson disease: Should the focus be on axons and synaptic terminals?

et al. 2019

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While current effective therapies are available for the symptomatic control of PD, treatments to halt the progressive neurodegeneration still do not exist. Loss of dopamine neurons in the SNc and dopamine terminals in the striatum drive the motor features of PD. Multiple lines of research point to several pathways which may contribute to dopaminergic neurodegeneration. These pathways include extensive axonal arborization, mitochondrial dysfunction, dopamine's biochemical properties, abnormal protein accumulation of α‐synuclein, defective autophagy and lysosomal degradation, and synaptic impairment. Thus, understanding the essential features and mechanisms of dopaminergic neuronal vulnerability is a major scientific challenge and highlights an outstanding need for fostering effective therapies against neurodegeneration in PD. This article, which arose from the Movement Disorders 2018 Conference, discusses and reviews the possible mechanisms underlying neuronal vulnerability and potential therapeutic approaches in PD. © 2019 International Parkinson and Movement Disorder Society

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Striatal Blood–Brain Barrier Opening in Parkinson's Disease Dementia: A Pilot Exploratory Study

et al. 2022

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Background Parkinson's disease (PD) exhibits a high prevalence of dementia as disease severity and duration progress. Focused ultrasound (FUS) has been applied for transient blood–brain barrier (BBB) opening of cortical regions in neurodegenerative disorders. The striatum is a primary target for delivery of putative therapeutic agents in PD. Objective Here, we report a prospective, single‐arm, nonrandomized, proof‐of‐concept, phase I clinical trial (NCT03608553 amended) in PD with dementia to test the safety and feasibility of striatal BBB opening in PD patients. Methods Seven PD patients with cognitive impairment were treated for BBB opening in the posterior putamen. This was performed in two sessions separated by 2 to 4 weeks, where the second session included bilateral putamina opening in 3 patients. Primary outcome measures included safety and feasibility of focal striatal BBB opening. Changes in motor and cognitive functions, magnetic resonance imaging (MRI), 18F‐fluorodopa (FDOPA), and β‐amyloid PET (positron emission tomography) images were determined. Results The procedure was feasible and well tolerated, with no serious adverse events. No neurologically relevant change in motor and cognitive (battery of neuropsychological tests) functions was recognized at follow‐up. MRI revealed putamen BBB closing shortly after treatment (24 hours to 14 days) and ruled out hemorrhagic and ischemic lesions. There was a discrete but significant reduction in β‐amyloid uptake in the targeted region and no change in FDOPA PET. Conclusions These initial results indicate that FUS‐mediated striatal BBB opening is feasible and safe and therefore could become an effective tool to facilitate the delivery of putative neurorestorative molecules in PD. © 2022 International Parkinson and Movement Disorder Society.

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Blood–brain barrier opening with focused ultrasound in experimental models of Parkinson's disease

Cited by 46 publications

References 86 publications

Focused ultrasound in Parkinson's disease: A twofold path toward disease modification

Focused ultrasound in Parkinson's disease: A twofold path toward disease modification

Neuronal vulnerability in Parkinson disease: Should the focus be on axons and synaptic terminals?

Striatal Blood–Brain Barrier Opening in Parkinson's Disease Dementia: A Pilot Exploratory Study

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