A multimodal Near-Infrared and MRI technique to assess cerebral metabolic changes in mouse models of neurological diseases
Date
2022-03-23
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Abstract
The central nervous system is highly dependent on oxidative metabolism. Adequate delivery, and consumption of oxygen are achieved via regulation of blood flow and oxygen or energy demand. These mechanisms are vulnerable to failure, which might affect the optimal function of the brain and eventually cause cellular damage and/or death. Disruptions in oxidative metabolism have been found in many neurological disorders, such as Multiple Sclerosis, Alzheimer's Disease, Parkinson’s Disease. These involve changes in the blood flow, the metabolic rate and levels of oxygen in the brain, and/or abnormalities in the mitochondria. This thesis focuses on developing, validating, and applying a multimodal method which combines Near-Infrared Spectroscopy (NIRS) and Magnetic Resonance Imaging (MRI), to non-invasively study oxidative metabolism in rodent cerebral cortex. The MRI provides information regarding the brain structure and the cerebral blood flow (CBF). The NIRS detects hemoglobin (Hb), and the mitochondrial enzyme cytochrome c oxidase (CCO) which are both strongly linked to oxygenation and metabolism. A new algorithm for measuring the absolute redox state of CCO from NIRS data, was introduced and validated. Oxygen saturation in the cerebral tissue (StO2) was assessed from the absolute concentration of deoxygenated, and total Hb. Oxygen Extraction Fraction (OEF) and CMRO2 were calculated using the modified Fick Principle. Challenges such as hypothermia, hypercapnia, and varying levels of oxygenation were applied to mice, to validate the absolute quantification of CMRO2, CBF, OEF, StO2 and CCO redox state, and investigate the association between these parameters. We applied the method to investigate oxidative metabolism in neurological disorders by studying the time course of metabolic changes in a cuprizone mouse model of demyelination and spontaneous remyelination. NIRS-MRI showed evidence of altered CCO redox state during cuprizone exposure, increased oxygenation and reduced metabolic rate associated with reduced myelination in the gray and white matter. Multimodal NIRS-MRI was capable to noninvasively assess parameters associated with oxidative metabolism. The development of such a technology may allow researchers and clinicians to follow the pathological progression and treatment response, of neurological diseases associated with mitochondrial dysfunction and abnormal oxidative metabolism.
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Keywords
MRI, NIRS, CMRO2, CBF, Cytochrome c oxidase, mouse models, cuprizone model
Citation
Hashem, M. (2022). A multimodal Near-Infrared and MRI technique to assess cerebral metabolic changes in mouse models of neurological diseases (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.