Browsing by Author "Nathoo, Nabeela"

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    Characterizing Susceptibility Weighted MRI in the Experimental Autoimmune Encephalomyelitis Mouse Model of Multiple Sclerosis
    (2014-10-07) Nathoo, Nabeela; Dunn, Jeff F.; Yong, V. Wee
    Susceptibility-based magnetic resonance imaging (MRI) methods have been used in multiple sclerosis (MS) patients for lesion detection, visualization of the venous vasculature and to show abnormal iron accumulation in the deep grey matter structures of the brain. The overarching goal of this thesis was to characterize one of the susceptibility-based MRI methods, susceptibility weighted imaging (SWI), in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. First, we investigated if SWI could detect lesions (or hypointensities) in the lumbar spinal cords and cerebella of EAE mice. We found that SWI hypointensities were present in a region-specific manner in the CNS of EAE mice, where most of these lesions were attributed to deoxyhemoglobin and a smaller number were due to parenchymal iron deposition. Next, we validated a method to identify deoxyhemoglobin-based SWI hypointensities in vivo which entailed combining SWI with hyperoxygenation. Following this, we sought to investigate when SWI hypointensities appear during the EAE disease course and how they change over the course of the disease. This was studied by carrying out serial SWI in vivo in naïve mice and mice immunized for EAE. Here, we found that SWI hypointensities are prominent before signs of motor dysfunction in EAE mice. SWI hypointensities were also observed to evolve over the disease course. Of note, the number of SWI hypointensities was always at a maximum before or at the same time as maximum motor dysfunction. Unlike EAE mice, the number of SWI hypointensities remained stable through all imaging time points in naïve mice, suggesting that SWI hypointensities are linked to EAE pathophysiology. Lastly we used SWI to assess treatment response to an anti-inflammatory treatment (dexamethasone) in EAE mice. This was carried out under the premise that SWI hypointensities may be linked to inflammation, so reducing inflammation could reduce the number of SWI hypointensities present. Our preliminary data suggest that SWI may be able to act as a surrogate marker of inflammation. Overall, findings from this thesis support the use of SWI in future studies in the EAE model to investigate the venous vasculature and parenchymal iron deposition.
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    Detecting Deoxyhemoglobin in Spinal Cord Vasculature of the Experimental Autoimmune Encephalomyelitis Mouse Model of Multiple Sclerosis Using Susceptibility MRI and Hyperoxygenation
    (PLOS ONE, 2015-05-18) Nathoo, Nabeela; Rogers, James A.; Yong, V. Wee; Dunn, Jeff F.
    Susceptibility-weighted imaging (SWI) detects hypointensities due to iron deposition and deoxyhemoglobin. Previously it was shown that SWI detects hypointensities in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS), most of which are due to intravascular deoxyhemoglobin, with a small proportion being due to iron deposition in the central nervous system parenchyma and demyelination. However, animals had to be sacrificed to differentiate these two types of lesions which is impractical for time course studies or for human application. Here, we proposed altering the inspired oxygen concentration during imaging to identify deoxyhemoglobin-based hypointensities in vivo. SWI was performed on lumbar spinal cords of naive control and EAE mice using 30% O2 then 100% O2. Some mice were imaged using 30% O2, 100% O2 and after perfusion. Most SWI-visible hypointensities seen with 30% O2 changed in appearance upon administration of 100% O2, and were not visible after perfusion. That hypointensities changed with hyperoxygenation indicates that they were caused by deoxyhemoglobin. We show that increasing the inspired oxygen concentration identifies deoxyhemoglobin-based hypointensities in vivo. This could be applied in future studies to investigate the contribution of vascular-based hypointensities with SWI in EAE and MS over time.
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    Detection of reduced interhemispheric cortical communication during task execution in multiple sclerosis patients using functional near-infrared spectroscopy
    (Society of Photo-optical Instrumentation Engineers, 2014-07-08) Jimenez, Jon J; Yang, Runze; Nathoo, Nabeela; Varshney, Vishal P; Golestani, Ali-Mohammad; Metz, Luanne M; Dunn, Jeff F
    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.
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    Gray matter hypoxia in the brain of the experimental autoimmune encephalomyelitis model of multiple sclerosis
    (2016-01-14) Johnson, Thomas W.; Dunn, Jeff F.; Wu, Ying; Nathoo, Nabeela; Rogers, James A.; Yong, V. Wee
    Background: Multiple sclerosis has a significant inflammatory component. As inflammation can induce and be modulated by hypoxia, the presence of hypoxia could provide clues about immune response regulation in MS. Objective: quantify oxygenation in gray matter (GM) of mice with the experimental autoimmune encephalomyelitis (EAE) model to determine if hypoxia exists in a demyelination model associated with chronic inflammation. Methods: C57BL/6 mice were implanted with a fiber-optic sensor in the cerebellum (n=13) and cortex (n=21). We measured PO2 in awake, unrestrained animals from baseline up to 36 days post-induction for EAE. Results: There were more days with hypoxia compared with hyperoxia (cerebellum: 13/67 vs. 7/67 days; cortex: 15/112 vs. 2/112). Cerebellum showed the largest differences between days 13-17, corresponding to high behavioral deficits. This occurred later for cortex (day 23). Hypoxia in the cortex correlated with increased behavioral deficits and increased variation (based on z-score comparisons with baseline and age-matched controls) in the cerebellum correlated with clinical deficits. Conclusions: The presence of hypoxia and increased variation in GM oxygenation indicates that oxygen may change enough to modulate the immune response. The cause may relate to increased metabolic dysfunction, disruption of neurovascular coupling or increased oxidative metabolism in activated microglia.
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    Hypoxia and Inflammation-Induced Disruptions of the Blood-Brain and Blood-Cerebrospinal Fluid Barriers Assessed Using a Novel T1-Based MRI Method
    (Springer Verlag, 2016-01) Nathoo, Nabeela; Jalal, Hamza; Natah, Sirajedin S.; Zhang, Qiong; Wu, Ying; Dunn, Jeffery F.
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    Iron in multiple sclerosis: roles in neurodegeneration and repair
    (Nature Publishing Group, 2014-07-08) Stephenson, Erin; Nathoo, Nabeela; Mahjoub, Yasamin; Dunn, Jeffery F.; Yong, V. Wee
    MRI and histological studies have shown global alterations in iron levels in the brains of patients with multiple sclerosis (MS), including increases in the iron stored by macrophages and microglia. Excessive free iron can be toxic, and accumulation of iron in MS has generally been thought to be detrimental. However, iron maintains the integrity of oligodendrocytes and myelin, and facilitates their regeneration following injury. The extracellular matrix, a key regulator of remyelination, might also modulate iron levels. This Review highlights key histological and MRI studies that have investigated changes in iron distribution associated with MS. Potential sources of iron, as well as iron regulatory proteins and the detrimental roles of excessive iron within the CNS, are also discussed, with emphasis on the importance of iron within cells for oxidative metabolism, proliferation and differentiation of oligodendrocytes, and myelination. In light of the beneficial and detrimental properties of iron within the CNS, we present considerations for treatments that target iron in MS. Such treatments must balance trophic and toxic properties of iron, by providing sufficient iron levels for remyelination and repair while avoiding excesses that might overwhelm homeostatic mechanisms and contribute to damage.
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    Iron Oxide as an MRI Contrast Agent for Cell Tracking
    (Libertas Academica, 2015-08-19) Korchinski, Daniel; Taha, Mai; Yang, Runze; Nathoo, Nabeela; Dunn, Jeff F.
    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.
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    A Tale of Two Methods: Combining Near-Infrared Spectroscopy with MRI for Studies of Brain Oxygenation and Metabolism
    (Kluwer, 2014-03-22) Dunn, Jeffrey F.; Nathoo, Nabeela; Yang, Runze
    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.
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    Understanding disease processes in multiple sclerosis through magnetic resonance imaging studies in animal models
    (Elsevier, 2014-04-24) Nathoo, Nabeela; Yong, V. Wee; Dunn, Jeffrey F.
    There are exciting new advances in multiple sclerosis (MS) resulting in a growing understanding of both the complexity of the disorder and the relative involvement of grey matter, white matter and inflammation. Increasing need for preclinical imaging is anticipated, as animal models provide insights into the pathophysiology ofthe disease. Magnetic resonance (MR)is the key imaging tool used to diagnose and to monitor disease progression in MS, and thus will be a cornerstone for future research. Although gadolinium-enhancing and T2 lesions on MRI have been useful for detecting MS pathology, they are not correlative of disability. Therefore, new MRI methods are needed. Such methods require validation in animal models. The increasing necessity for MRI of animal models makes it critical and timely to understand what research has been conducted in this area and what potential there is for use of MRI in preclinical models of MS. Here, we provide a review of MRI and magnetic resonance spectroscopy (MRS) studies that have been carried out in animal models of MS that focus on pathology. We compare the MRI phenotypes of animals and patients and provide advice on how best to use animal MR studies to increase our understanding of the linkages between MR and pathology in patients. This review describes how MRI studies of animal models have been, and will continue to be, used in the ongoing effort to understand MS.
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    Using magnetic resonance imaging in animal models to guide drug development in multiple sclerosis
    (2013-11-21) Nathoo, Nabeela; Yong, V Wee; Dunn, Jeffrey F.; Beketskaia, Maria
    Major advances are taking place in the development of therapeutics for multiple sclerosis (MS), with a move past traditional immunomodulatory/immunosuppressive therapies toward medications aimed at promoting remyelination or neuroprotection. With an increase in diversity of MS therapies comes the need to assess the effectiveness of such therapies. Magnetic resonance imaging (MRI) is one of the main tools used to evaluate the effectiveness of MS therapeutics in clinical trials. As all new therapeutics for MS are tested in animal models first, it is logical that MRI be incorporated into preclinical studies assessing therapeutics. Here, we review key papers showing how MR imaging has been combined with a range of animal models to evaluate potential therapeutics for MS. We also advise on how to maximize the potential for incorporating MRI into preclinical studies evaluating possible therapeutics for MS, which should improve the likelihood of discovering new medications for the condition.