Dataset Information

Real-Time MRI Guidance for Reproducible Hyperosmolar Opening of the Blood-Brain Barrier in Mice.

ABSTRACT: The blood-brain barrier (BBB) prevents effective delivery of most therapeutic agents to the brain. Intra-arterial (IA) infusion of hyperosmotic mannitol has been widely used to open the BBB and improve parenchymal targeting, but the extent of BBB disruption has varied widely with therapeutic outcomes often being unpredictable. In this work, we show that real-time MRI can enable fine-tuning of the infusion rate to adjust and predict effective and local brain perfusion in mice, and thereby can be allowed for achieving the targeted and localized BBB opening (BBBO). Both the reproducibility and safety are validated by MRI and histology. The reliable and reproducible BBBO we developed in mice will allow cost-effective studies on the biology of the BBB and drug delivery to the brain. In addition, the IA route for BBBO also permits subsequent IA delivery of a specific drug during the same procedure and obtains high targeting efficiency of the therapeutic agent in the targeted tissue, which has great potential for future clinical translation in neuro-oncology, regenerative medicine and other neurological applications.

SUBMITTER: Chu C

PROVIDER: S-EPMC6212512 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Real-Time MRI Guidance for Reproducible Hyperosmolar Opening of the Blood-Brain Barrier in Mice.

Chu Chengyan C Liu Guanshu G Janowski Miroslaw M Bulte Jeff W M JWM Li Shen S Pearl Monica M Walczak Piotr P

Frontiers in neurology 20181026

The blood-brain barrier (BBB) prevents effective delivery of most therapeutic agents to the brain. Intra-arterial (IA) infusion of hyperosmotic mannitol has been widely used to open the BBB and improve parenchymal targeting, but the extent of BBB disruption has varied widely with therapeutic outcomes often being unpredictable. In this work, we show that real-time MRI can enable fine-tuning of the infusion rate to adjust and predict effective and local brain perfusion in mice, and thereby can be ...[more]

PMID: 30416485

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Project description:Background : Focused ultrasound (FUS) in combination with microbubbles has recently shown great promise in facilitating blood-brain barrier (BBB) opening for drug delivery and immunotherapy in Alzheimer's disease (AD). However, it is currently limited to systems integrated within the MRI suites or requiring post-surgical implants, thus restricting its widespread clinical adoption. In this pilot study, we investigate the clinical safety and feasibility of a portable, non-invasive neuronavigation-guided FUS (NgFUS) system with integrated real-time 2-D microbubble cavitation mapping. Methods : A phase 1 clinical study with mild to moderate AD patients (N = 6) underwent a single session of microbubble-mediated NgFUS to induce transient BBB opening (BBBO). Microbubble activity under FUS was monitored with real-time 2-D cavitation maps and dosing to ensure the efficacy and safety of the NgFUS treatment. Post-operative MRI was used for BBB opening and closure confirmation as well as safety assessment. Changes in AD biomarker levels in both blood serum and extracellular vesicles (EVs) were evaluated, while changes in amyloid-beta (Aβ) load in the brain were assessed through 18F-florbetapir PET. Results : BBBO was achieved in 5 out of 6 subjects with an average volume of 983 ± 626 mm3 following FUS at the right frontal lobe both in white and gray matter regions. The outpatient treatment was completed within 34.8 ± 10.7 min. Cavitation dose significantly correlated with the BBBO volume (R 2 > 0.9, N = 4), demonstrating the portable NgFUS system's capability of predicting opening volumes. The cavitation maps co-localized closely with the BBBO location, representing the first report of real-time transcranial 2-D cavitation mapping in the human brain. Larger opening volumes correlated with increased levels of AD biomarkers, including Aβ42 (R 2 = 0.74), Tau (R 2 = 0.95), and P-Tau181 (R 2 = 0.86), assayed in serum-derived EVs sampled 3 days after FUS (N = 5). From PET scans, subjects showed a lower Aβ load increase in the treated frontal lobe region compared to the contralateral region. Reduction in asymmetry standardized uptake value ratios (SUVR) correlated with the cavitation dose (R 2 > 0.9, N = 3). Clinical changes in the mini-mental state examination over 6 months were within the expected range of cognitive decline with no additional changes observed as a result of FUS. Conclusion : We showed the safety and feasibility of this cost-effective and time-efficient portable NgFUS treatment for BBBO in AD patients with the first demonstration of real-time 2-D cavitation mapping. The cavitation dose correlated with BBBO volume, a slowed increase in pathology, and serum detection of AD proteins. Our study highlights the potential for accessible FUS treatment in AD, with or without drug delivery.

Project description:BackgroundFocused ultrasound (FUS) in combination with microbubbles has recently shown great promise in facilitating blood-brain barrier (BBB) opening for drug delivery and immunotherapy in Alzheimer's disease (AD). However, it is currently limited to systems integrated within the MRI suites or requiring post-surgical implants, thus restricting its widespread clinical adoption. In this pilot study, we investigate the clinical safety and feasibility of a portable, non-invasive neuronavigated FUS system with integrated real-time 2D microbubble cavitation mapping.MethodsA phase 1 clinical study with mild to moderate AD patients (N=6) underwent a single session of microbubble-mediated FUS to induce transient BBB opening (BBBO). Microbubble activity under FUS was monitored with real-time 2-D cavitation maps and dosing to ensure the efficacy and safety of the FUS treatment. Post-operative MRI was used for BBB opening and closure confirmation as well as safety assessment. Changes in AD biomarker levels in both blood serum and extracellular vesicles (EVs) were evaluated, while changes in amyloid-beta (Aβ) load in the brain were assessed through 18F-Florbetapir PET.ResultsBBBO was achieved in 5 out of 6 subjects with an average volume of 983±626 mm3 following FUS at the right frontal lobe both in white and gray matter regions. The outpatient treatment was completed within 34.8±10.7 min. Cavitation dose significantly correlated with the BBBO volume (R2>0.9, N=4), demonstrating the portable FUS system's capability of predicting opening volumes. The cavitation maps co-localized closely with the BBBO location, representing the first report of real-time transcranial 2-D cavitation mapping in the human brain. Larger opening volumes correlated with increased levels of AD biomarkers, including Aβ42/Aβ40 (R2=0.74), Tau (R2=0.95), and P-Tau181 (R2=0.86), assayed in serum-derived EVs sampled 3 days after FUS (N=5). From PET scans, subjects showed a lower Aβ load increase in the treated frontal lobe region compared to the contralateral region. Reduction in asymmetry standardized uptake value ratios (SUVR) correlated with the harmonic cavitation dose (R2>0.9, N=3). Clinical changes in the mini-mental state examination over 6 months were within the expected range of cognitive decline with no additional changes observed as a result of FUS.ConclusionSafety and feasibility of this cost-efficient and portable FUS for BBBO in AD patients were demonstrated with real-time mapping correlating with BBBO volume and a reduction in pathology, as well as serum detection of the AD proteins, Aβ and tau. Our study suggest the potential for accessible FUS treatment in AD, with or without drug delivery.

Project description:Plasmodium falciparum malaria is responsible for nearly one million annual deaths worldwide. Because of the difficulty in monitoring the pathogenesis of cerebral malaria in humans, we conducted a study in various mouse models to better understand disease progression in experimental cerebral malaria (ECM). We compared the effect on the integrity of the blood brain barrier (BBB) and the histopathology of the brain of P. berghei ANKA, a known ECM model, P. berghei NK65, generally thought not to induce ECM, P. yoelii 17XL, originally reported to induce human cerebral malaria-like histopathology, and P. yoelii YM. As expected, P. berghei ANKA infection caused neurological signs, cerebral hemorrhages, and BBB dysfunction in CBA/CaJ and Swiss Webster mice, while Balb/c and A/J mice were resistant. Surprisingly, PbNK induced ECM in CBA/CaJ mice, while all other mice were resistant. P. yoelii 17XL and P. yoelii YM caused lethal hyperparasitemia in all mouse strains; histopathological alterations, BBB dysfunction, or neurological signs were not observed. Intravital imaging revealed that infected erythrocytes containing mature parasites passed slowly through capillaries making intimate contact with the endothelium, but did not arrest. Except for relatively rare microhemorrhages, mice with ECM presented no obvious histopathological alterations that would explain the widespread disruption of the BBB. Intravital imaging did reveal, however, that postcapillary venules, but not capillaries or arterioles, from mice with ECM, but not hyperparasitemia, exhibit platelet marginalization, extravascular fibrin deposition, CD14 expression, and extensive vascular leakage. Blockage of LFA-1 mediated cellular interactions prevented leukocyte adhesion, vascular leakage, neurological signs, and death from ECM. The endothelial barrier-stabilizing mediators imatinib and FTY720 inhibited vascular leakage and neurological signs and prolonged survival to ECM. Thus, it appears that neurological signs and coma in ECM are due to regulated opening of paracellular-junctional and transcellular-vesicular fluid transport pathways at the neuroimmunological BBB.

Dataset Information

Real-Time MRI Guidance for Reproducible Hyperosmolar Opening of the Blood-Brain Barrier in Mice.

Publications

Real-Time MRI Guidance for Reproducible Hyperosmolar Opening of the Blood-Brain Barrier in Mice.

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