noninvasive focused ultrasound accelerates glymphatic...
TRANSCRIPT
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Stanford University
Noninvasive Focused Ultrasound Accelerates Glymphatic Transport to Bypass the Blood-Brain Barrier
Muna Aryal, PhDPostdoctoral Fellow
Department of Radiology
Mentors: Drs. Raag Airan & Jeremy Dahl
SCIT SeminarJanuary 29, 2020
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Outline
q Introduction • Meningeal Lymphatic• Glymphatic Pathway
q Ultrasonic Glymphatic Control
q Conclusions
q Future Work
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A Garbage Truck of The Brain: Meningeal Lymphatic
Louveau et al., Nature 2015.
• Immune cells• Cerebral spinal fluid• Macromolecules
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Stanford UniversityNedergaard et al., Science 2013.
A Garbage Truck of The Brain: Glymphatic PathwayProteins (Amyloid-beta (Ab), Tau oligomers
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Glymphatic Dysfunction and Therapeuticsq Clearance efficacy can decay
• Healthy aging• Alzheimer• Traumatic brain injury, • Subarachnoid hemorrhage • Strokes (Hemorrhagic, Ischemic)• Idiopathic normal pressure
hydrocephalus• Diabetes Mellitus Type 2
Nedergaard et al., Science 2013. Meng et al, Ann Neurol. 2019. 4/25
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Stanford UniversityNedergaard et al., Science 2013. Meng et al, Ann Neurol. 2019.
Glymphatic Dysfunction and Therapeuticsq Clearance efficacy can decay
• Healthy aging• Alzheimer• Traumatic brain injury, • Subarachnoid hemorrhage • Strokes (Hemorrhagic, Ischemic)• Idiopathic normal pressure
hydrocephalus• Diabetes Mellitus Type 2
q Glymphatic Transport: novel therapeutic target to optimize and maintain the brain health
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Approaches to Accelerates Glymphatic Flow
• Physical exercise• Changes in body posture• Intake of omega-3
polyunsaturated fatty acids• Low dose alcohol (0.5 g/kg)
Nedergaard et al., Science 2013. Meng et al, Ann Neurol. 2019. 5/25
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Approaches to Accelerates Glymphatic Flow
• Physical exercise• Changes in body posture• Intake of omega-3
polyunsaturated fatty acids• Low dose alcohol (0.5 g/kg)
• FUS-BBBO clearing the Ab in alzhiemer’s disease model
Nedergaard et al., Science 2013. Meng et al, Ann Neurol. 2019. 5/25
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Stanford University
Approaches to Accelerates Glymphatic Flow
• Physical exercise• Changes in body posture• Intake of omega-3
polyunsaturated fatty acids• Low dose alcohol (0.5 g/kg)
• FUS-BBBO clearing the Ab in alzhiemer’s disease model
Nedergaard et al., Science 2013. Meng et al, Ann Neurol. 2019. 5/25
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Limitations of BBBO
• Spatial Resolution is limited for neurodegenerative diseases that needs global treatment like Alzheimer’s and infiltrating/metastatic tumor and for other
• Disrupting the BBB by FUS induces sterile inflammation, Kovacs et al. PNAS 2017
• BBB breakdown is an early biomarker of human cognitive dysfunction, Nation et al. Nature medicine 2019
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Supportive Data
• BBBO helps to distribute drug homogeneously in tumor
• Ultrasound is accelerating the bulk flow of interstitial fluid
N+F
T+FT-F
N-F
Segmentation map of MALDI-MS imaging
BBBOTumor
No BBBOTumor
(Drug: Maroon color in map)BBBOTumor
No BBBOTumor
Hematoxylin and Eosin Staining
Aryal et al., Under Preparation.8/25
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Stanford UniversityJung B, et al. J Control Release. 2019
Supportive Data
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Supportive Data
Hersh et al., PLoS One. 2018, 10/25
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Supportive Data
Nicodemus et al. Alzheimers Dement (N Y). 201911/25
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Biological Agent Delivery via BBBO
• Panitumumumab: Epidermal growth factor receptor inhibitor cancer drug (biological therapy)
• Optically-labeled Panitumumumab: Pan800
• Test: BBBO-based drug delivery efficacy
TumorBBBO
Tumor No BBBO
HealthyBBBO
Preliminary Results22/25
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Thank you