Runze Yang

Iron Oxide as an MRI Contrast Agent for Cell Tracking

Iron oxide contrast agents have been combined with magnetic resonance imaging for cell tracking. In this review, we discuss coating properties and provide an overview of ex vivo and in vivo labeling of different cell types, including stem cells, red blood cells, and monocytes/macrophages. Furthermore, we provide examples of applications of cell tracking with iron contrast agents in stroke, multiple sclerosis, cancer, arteriovenous malformations, and aortic and cerebral aneurysms. Attempts at quantifying iron oxide concentrations and other vascular properties are examined. We advise on designing studies using iron contrast agents including methods for validation.

MRI monitoring of monocytes to detect immune stimulating treatment response in brain tumor

Background Glioblastoma (GBM) is an aggressive brain cancer with a poor prognosis. The use of immune therapies to treat GBM has become a promising avenue of research. It was shown that amphotericin B (Amp B) can stimulate the innate immune system and suppress the growth of brain tumor initiating cells (BTICs). However, it is not feasible to use histopathology to determine immune activation in patients. We developed an MRI technique that can rapidly detect a therapeutic response in animals treated with drugs that stimulate innate immunity. Ultra-small iron oxide nanoparticles (USPIOs) are MRI contrast agents that have been widely used for cell tracking. We hypothesized that the increased monocyte infiltration into brain tumors due to Amp B can be detected using USPIO-MRI, providing an indicator of early drug response. Methods We implanted human BTICs into severe combined immunodeficient mice and allowed the tumor to establish before treating the animals with either Amp B or vehicle and then imaged them using MRI with USPIO (ferumoxytol) contrast. Results After 7 days of treatment, there was a significantly decreased T2* in the tumor of Amp B but not vehicle animals, suggesting that USPIO is carried into the tumor by monocytes. We validated our MRI results with histopathology and confirmed that Amp B-treated animals had significantly higher levels of macrophage/microglia that were colocalized with iron staining in their brain tumor compared with vehicle mice. Conclusion USPIO-MRI is a promising method of rapidly assessing the efficacy of anticancer drugs that stimulate innate immunity.

Reduced cortical microvascular oxygenation in multiple sclerosis: a blinded, case-controlled study using a novel quantitative near-infrared spectroscopy method.

Hypoxia (low oxygen) is associated with many brain disorders as well as inflammation, but the lack of widely available technology has limited our ability to study hypoxia in human brain. Multiple sclerosis (MS) is a poorly understood neurological disease with a significant inflammatory component which may cause hypoxia. We hypothesized that if hypoxia were to occur, there should be reduced microvascular hemoglobin saturation (StO2). In this study, we aimed to determine if reduced StO2 can be detected in MS using frequency domain near-infrared spectroscopy (fdNIRS). We measured fdNIRS data in cortex and assessed disability of 3 clinical isolated syndrome (CIS), 72 MS patients and 12 controls. Control StO2 was 63.5 ± 3% (mean ± SD). In MS patients, 42% of StO2 values were more than 2 × SD lower than the control mean. There was a significant relationship between StO2 and clinical disability. A reduced microvascular StO2 is supportive (although not conclusive) that there may be hypoxic regions in MS brain. This is the first study showing how quantitative NIRS can be used to detect reduced StO2 in patients with MS, opening the door to understanding how microvascular oxygenation impacts neurological conditions.

Studying cerebral hemodynamics and metabolism using simultaneous near-infrared spectroscopy and transcranial Doppler ultrasound: a hyperventilation and caffeine study.

Caffeine is one of the most widely consumed psycho‐stimulants in the world, yet little is known about its effects on brain oxygenation and metabolism. Using a double‐blind, placebo‐controlled, randomized cross‐over study design, we combined transcranial Doppler ultrasound (TCD) and near‐infrared spectroscopy (NIRS) to study caffeines effect on middle cerebral artery peak blood flow velocity (Vp), brain tissue oxygenation (StO2), total hemoglobin (tHb), and cerebral oxygen metabolism (CMRO2) in five subjects. Hyperventilation‐induced hypocapnia served as a control to verify the sensitivity of our measurements. During hypocapnia (~16 mmHg below resting values), Vp decreased by 40.0 ± 2.4% (95% CI, P < 0.001), while StO2 and tHb decreased by 2.9 ± 0.3% and 2.6 ± 0.4%, respectively (P = 0.003 and P = 0.002, respectively). CMRO2, calculated using the Fick equation, was reduced by 29.3 ± 9% compared to the isocapnic‐euoxia baseline (P < 0.001). In the pharmacological experiments, there was a significant decrease in Vp, StO2, and tHb after ingestion of 200 mg of caffeine compared with placebo. There was no significant difference in CMRO2 between caffeine and placebo. Both showed a CMRO2 decline compared to baseline showing the importance of a placebo control. In conclusion, this study showed that profound hypocapnia impairs cerebral oxidative metabolism. We provide new insight into the effects of caffeine on cerebral hemodynamics. Moreover, this study showed that multimodal NIRS/TCD is an excellent tool for studying brain hemodynamic responses to pharmacological interventions and physiological challenges.

Near-infrared measurements of brain oxygenation in stroke

Abstract. We investigated the feasibility of using frequency-domain near-infrared spectroscopy (fdNIRS) to study brain oxygenation in the first few hours of stroke onset. The OxiplexTS® fdNIRS system was used in this study. Using a standard probing protocol based on surface landmarks, we measured brain tHb and StO2 in healthy volunteers, cadavers, and acute stroke patients within 9 h of stroke onset and 3 days later. We obtained measurements from 11 controls, 5 cadavers, and 5 acute stroke patients. StO2 values were significantly lower in cadavers compared to the controls and stroke patients. Each stroke patient had at least one area with reduced StO2 on the stroke side compared to the contralateral side. The evolution of tHb and StO2 at 3 days differed depending on whether a large infarct occurred. This study shows the proof of principle that quantified measurements of brain oxygenation using NIRS could be used in the hectic environment of acute stroke management. It also highlights the current technical limitations and future challenges in the development of this unique bedside monitoring tool for stroke.

Detection of reduced interhemispheric cortical communication during task execution in multiple sclerosis patients using functional near-infrared spectroscopy

Abstract. Multiple sclerosis (MS) impairs brain activity through demyelination and loss of axons. Increased brain activity is accompanied by increases in microvascular hemoglobin oxygen saturation (oxygenation) and total hemoglobin, which can be measured using functional near-infrared spectroscopy (fNIRS). Due to the potentially reduced size and integrity of the white matter tracts within the corpus callosum, it may be expected that MS patients have reduced functional communication between the left and right sides of the brain; this could potentially be an indicator of disease progression. To assess interhemispheric communication in MS, we used fNIRS during a unilateral motor task and the resting state. The magnitude of the change in hemoglobin parameters in the motor cortex was significantly reduced in MS patients during the motor task relative to healthy control subjects. There was also a significant decrease in interhemispheric communication between the motor cortices (expressed as coherence) in MS patients compared to controls during the motor task, but not during the resting state. fNIRS assessment of interhemispheric coherence during task execution may be a useful marker in disorders with white matter damage or axonal loss, including MS.

Monitoring angiogenesis using a human compatible calibration for broadband near-infrared spectroscopy

Abstract. Angiogenesis is a hallmark of many conditions, including cancer, stroke, vascular disease, diabetes, and high-altitude exposure. We have previously shown that one can study angiogenesis in animal models by using total hemoglobin (tHb) as a marker of cerebral blood volume (CBV), measured using broadband near-infrared spectroscopy (bNIRS). However, the method was not suitable for patients as global anoxia was used for the calibration. Here we determine if angiogenesis could be detected using a calibration method that could be applied to patients. CBV, as a marker of angiogenesis, is quantified in a rat cortex before and after hypoxia acclimation. Rats are acclimated at 370-mmHg pressure for three weeks, while rats in the control group are housed under the same conditions, but under normal pressure. CBV increased in each animal in the acclimation group. The mean CBV (%volume/volume) is 3.49%±0.43% (mean±SD) before acclimation for the experimental group, and 4.76%±0.29% after acclimation. The CBV for the control group is 3.28%±0.75%, and 3.09%±0.48% for the two measurements. This demonstrates that angiogenesis can be monitored noninvasively over time using a bNIRS system with a calibration method that is compatible with human use and less stressful for studies using animals.

A Tale of Two Methods: Combining Near-Infrared Spectroscopy with MRI for Studies of Brain Oxygenation and Metabolism

Combining magnetic resonance imaging (MRI) with near-infrared spectroscopy (NIRS) leads to excellent synergies which can improve the interpretation of either method and can provide novel data with respect to measuring brain oxygenation and metabolism. MRI has good spatial resolution, can detect a range of physiological parameters and is sensitive to changes in deoxyhemoglobin content. NIRS has lower spatial resolution, but can detect, and with specific technologies, quantify, deoxyhemoglobin, oxyhemoglobin, total hemoglobin and cytochrome oxidase. This paper reviews the application of both methods, as a multimodal technology, for assessing changes in brain oxygenation that may occur with changes in functional activation state or metabolic rate. Examples of hypoxia and ischemia are shown. Data support the concept of reduced metabolic rate resulting from hypoxia/ischemia and that metabolic rate in brain is not close to oxygen limitation during normoxia. We show that multimodal MRI and NIRS can provide novel information for studies of brain metabolism.

Multiple sclerosis disease progression: Contributions from a hypoxia–inflammation cycle:

Hypoxia has been associated with multiple sclerosis (MS) and is an important area of research. Hypoxia can exacerbate inflammation via the prolylhydroxylase pathway. Inflammation can also trigger hypoxia by damaging mitochondria and endothelial cells to impair blood flow regulation. We hypothesize that there is a “hypoxia–inflammation cycle” in MS which plays an important role in MS disease progression. Therapies that break this cycle may be an interesting area of exploration for treatment of MS.

In Vivo MR Imaging of Tumor-Associated Macrophages: The Next Frontier in Cancer Imaging

There is a complex interaction between cancer and the immune system. Tumor-associated macrophages (TAMs) can be subverted by the cancer to adopt a pro-tumor phenotype to aid tumor growth. These anti-inflammatory, pro-tumor TAMs have been shown to contribute to a worsened outcome in several different types of cancer. Various strategies aimed at combating the pro-tumor TAMs have been developed. Several therapies, such as oncolytic viral therapy and high-intensity focused ultrasound, have been shown to stimulate TAMs and suppress tumor growth. Targeting TAMs is a promising way to combat cancer, but sensitive imaging methods that are capable of detecting these therapeutic responses are needed. A promising idea is to use imaging contrast agents to label TAMs to determine their relative number and location within, and around the tumor. This can provide information about the efficacy of TAM depletion therapies, as well as macrophage-stimulating therapies. In this review, we describe various in vivo MRI methods capable of tracking TAMs, and conclude with a short section on tracking TAMs in patients.