in-vivo-imaging-cerebrospinal-fluid-transport-through-intact-mouse

In Vivo Imaging of Cerebrospinal Fluid Transport through the Intact Mouse Skull using Fluorescence Macroscopy

Cerebrospinal fluid (CSF) flow in rodents has largely been studied using ex vivo quantification of tracers. Techniques such as two-photon microscopy and ...

the-development-ultrasound-intervention-diagnosis-treatment-non

The Development of Ultrasound Intervention in the Diagnosis and Treatment of Non-breast Superficial and Abdominal Diseases

Interventional ultrasound is undergoing a paradigm shift from a traditional diagnostic adjunct to a diversified therapeutic platform, particularly in ...

University of Rochester Medical Center

Qinghai Red Cross Hospital

Despite the initial promise of immunotherapy for CNS disease, multiple recent clinical trials have failed. This may be due in part to characteristically low penetration of antibodies to cerebrospinal fluid (CSF) and brain parenchyma, resulting in poor target engagement. We here utilized transcranial macroscopic imaging to noninvasively evaluate in vivo delivery pathways of CSF fluorescent tracers. Tracers in CSF proved to be distributed through a brain-wide network of periarterial spaces, previously denoted as the glymphatic system. CSF tracer entry was enhanced approximately 3-fold by increasing plasma osmolality without disruption of the blood-brain barrier. Further, plasma hyperosmolality overrode the inhibition of glymphatic transport that characterizes the awake state and reversed glymphatic suppression in a mouse model of Alzheimer's disease. Plasma hyperosmolality enhanced the delivery of an amyloid-β (Aβ) antibody, obtaining a 5-fold increase in antibody binding to Aβ plaques. Thus, manipulation of glymphatic activity may represent a novel strategy for improving penetration of therapeutic antibodies to the CNS.

Transcranial optical imaging reveals a pathway for optimizing the delivery of immunotherapeutics to the brain.

Flow of cerebrospinal fluid (CSF) through perivascular spaces (PVSs) in the brain is important for clearance of metabolic waste. Arterial pulsations are thought to drive flow, but this has never been quantitatively shown. We used particle tracking to quantify CSF flow velocities in PVSs of live mice. CSF flow is pulsatile and driven primarily by the cardiac cycle. The speed of the arterial wall matches that of the CSF, suggesting arterial wall motion is the principal driving mechanism, via a process known as perivascular pumping. Increasing blood pressure leaves the artery diameter unchanged but changes the pulsations of the arterial wall, increasing backflow and thereby reducing net flow in the PVS. Perfusion-fixation alters the normal flow direction and causes a 10-fold reduction in PVS size. We conclude that particle tracking velocimetry enables the study of CSF flow in unprecedented detail and that studying the PVS in vivo avoids fixation artifacts.

Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension.

The glymphatic system is a brain-wide clearance pathway; its impairment contributes to the accumulation of amyloid-β. Influx of cerebrospinal fluid (CSF) depends upon the expression and perivascular localization of the astroglial water channel aquaporin-4 (AQP4). Prompted by a recent failure to find an effect of  knock-out (KO) on CSF and interstitial fluid (ISF) tracer transport, five groups re-examined the importance of AQP4 in glymphatic transport. We concur that CSF influx is higher in wild-type mice than in four different  KO lines and in one line that lacks perivascular AQP4 ( KO). Meta-analysis of all studies demonstrated a significant decrease in tracer transport in KO mice and rats compared to controls. Meta-regression indicated that anesthesia, age, and tracer delivery explain the opposing results. We also report that intrastriatal injections suppress glymphatic function. This validates the role of AQP4 and shows that glymphatic studies must avoid the use of invasive procedures.

Aquaporin-4-dependent glymphatic solute transport in the rodent brain.

Drug delivery to the central nervous system remains a major problem due to biological barriers. The blood-brain-barrier can be bypassed by administering drugs intrathecally directly to the cerebrospinal fluid (CSF). The glymphatic system, a network of perivascular spaces promoting fluid exchange between CSF and interstitial space, could be utilized to enhance convective drug delivery from the CSF to the parenchyma. Glymphatic flow is highest during sleep and anesthesia regimens that induce a slow-wave sleep-like state. Here, using mass spectrometry and fluorescent imaging techniques, we show that the clinically used α-adrenergic agonist dexmedetomidine that enhances EEG slow-wave activity, increases brain and spinal cord drug exposure of intrathecally administered drugs in mice and rats. Using oxycodone, naloxone, and an IgG-sized antibody as relevant model drugs we demonstrate that modulation of glymphatic flow has a distinct impact on the distribution of intrathecally administered therapeutics. These findings can be exploited in the clinic to improve the efficacy and safety of intrathecally administered therapeutics.

Dexmedetomidine enhances glymphatic brain delivery of intrathecally administered drugs.

Cystic echinococcosis (CE) is a global public health problem associated with a high overall disease burden. Multiple organ systems are involved in approximately 20% of cases, and treatment is challenging and rarely reported. In this study, we described microwave ablation (MWA) combining surgery for the treatment of a multiorgan CE patient. The patient underwent percutaneous MWA for a hepatic CE3b lesion and exploratory resection of the pelvic cavity lesions. The hepatic lesion was effectively treated by MWA, and invasiveness was reduced by avoiding hepatectomy. The patient had a favorable prognosis at a 20-month's follow-up. More studies are needed to evaluate its usefulness in CE treatment.

Microwave ablation combining surgery for the treatment of multiorgan cystic echinococcosis: A case report.

Misclassifications of hepatic alveolar echinococcosis (HAE) as intrahepatic cholangiocarcinoma (ICC) may lead to inappropriate treatment strategies. The aim of this study was to explore the differential diagnosis with conventional ultrasound and contrast-enhanced ultrasound (CEUS).

Differential diagnosis between hepatic alveolar echinococcosis and intrahepatic cholangiocarcinoma with conventional ultrasound and contrast-enhanced ultrasound.

ArticleTotal : 2	Year
Publication title Cited by 26	2019
Publication title	2026

Article	Year
Transcranial optical imaging reveals a pathway for optimizing the delivery of immunotherapeutics to the brain. JCI insight\| PubMed ID: 30333324	2018
Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension. Nature communications\| PubMed ID: 30451853	2018
Aquaporin-4-dependent glymphatic solute transport in the rodent brain. eLife\| PubMed ID: 30561329	2018
Dexmedetomidine enhances glymphatic brain delivery of intrathecally administered drugs. Journal of controlled release : official journal of the Controlled Release Society\| PubMed ID: 31067483	2019
Microwave ablation combining surgery for the treatment of multiorgan cystic echinococcosis: A case report. Parasitology international\| PubMed ID: 31026594	2020
Differential diagnosis between hepatic alveolar echinococcosis and intrahepatic cholangiocarcinoma with conventional ultrasound and contrast-enhanced ultrasound. BMC medical imaging\| PubMed ID: 32854653	2020

Ting Du

Biography

JoVE Journal Publications

Other Publications