Abstract
Alzheimer's disease is a neurodegenerative disorder typified by the accumulation of a small protein, beta-amyloid, which aggregates and is the primary component of amyloid plaques. Many new therapeutic and diagnostic agents for reducing amyloid plaques have limited efficacy in vivo because of poor transport across the blood-brain barrier. Here we demonstrate that low-intensity focused ultrasound with a microbubble contrast agent may be used to transiently disrupt the blood-brain barrier, allowing non-invasive, localized delivery of imaging fluorophores and immunotherapeutics directly to amyloid plaques. We administered intravenous Trypan blue, an amyloid staining red fluorophore, and anti-amyloid antibodies, concurrently with focused ultrasound therapy in plaque-bearing, transgenic mouse models of Alzheimer's disease with amyloid pathology. MRI guidance permitted selective treatment and monitoring of plaque-heavy anatomical regions, such as the hippocampus. Treated brain regions exhibited 16.5±5.4-fold increase in Trypan blue fluorescence and 2.7±1.2-fold increase in anti-amyloid antibodies that localized to amyloid plaques. Ultrasound-enhanced delivery was consistently reproduced in two different transgenic strains (APPswe:PSEN1dE9, PDAPP), across a large age range (9–26 months), with and without MR guidance, and with little or no tissue damage. Ultrasound-mediated, transient blood-brain barrier disruption allows the delivery of both therapeutic and molecular imaging agents in Alzheimer's mouse models, which should aid pre-clinical drug screening and imaging probe development. Furthermore, this technique may be used to deliver a wide variety of small and large molecules to the brain for imaging and therapy in other neurodegenerative diseases.
Highlights
Neurodegenerative diseases are difficult to treat, in part because of the blood-brain barrier (BBB), a composite of highly specialized endothelial and perivascular structures that limit transport of molecules into the brain
Aged (11–12 month-old), double transgenic mice (n = 2) expressing APPswe and PSEN1dE9 mutations were treated with MRI-guided focused ultrasound (FUS)-MB (Figure 1), and received Trypan blue
BBB-disruption was confirmed in vivo with gadolinium-based, contrast-enhanced MRI (Figure 2)
Summary
Neurodegenerative diseases are difficult to treat, in part because of the blood-brain barrier (BBB), a composite of highly specialized endothelial and perivascular structures that limit transport of molecules into the brain. Many large biological molecules, such as antibodies and siRNA, cannot be modified to cross the BBB passively. A generic, non-invasive technique to deliver drugs to the brain would allow preclinical efficacy screening and facilitate basic research with biological agents. We and others have shown that low-intensity, focused ultrasound (FUS) administered with microbubbles (MB) (here termed FUS-MB therapy), can transiently disrupt the blood-brain barrier [3,4]. At frequencies suitable for non-invasive trans-skull focusing [5], FUS-MB causes BBB-disruption only in the transducer focal volume, which can be selected in real-time by magnetic resonance (MR) imaging for precise anatomical delivery. FUS-MB has not been applied to neurodegenerative disorders, a broad class of diseases that is largely refractory to current diagnostic and therapeutic approaches
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