4D Oxy-Wavelet MRI as a Non-Invasive Biomarker of Brain Mitochondrial Function In Vivo
Abstract
This proposal addresses the FY21 PRMRP Topic Area Mitochondria Disease, with a specific focus on the Area of Encouragement, Identification and testing of non-invasive techniques and biomarkers to monitor mitochondrial function, aid in clinical diagnosis, and/or evaluate therapeutic efficacy. This proposal will optimize and validate a form of functional magnetic resonance imaging (fMRI) that we call Oxy-wavelet MRI as a non-invasive biomarker of mitochondrial function in vivo. An Oxy-wavelet MRI scan simultaneously monitors oxygen homeostasis and structural properties in 72 regions of the brain with high-resolution and may be useful for detecting mitochondrial dysfunction in both rare genetic mitochondrial diseases as well as brain injury or diseases where mitochondrial dysfunction is secondary and may affect only certain brain structures. Preliminary data demonstrate its applicability to the fetal mouse brains, indicating its translational utility for diagnosis not only in children and adults, but also prenatally in developing fetuses. Mitochondrial dysfunction is a critical element for wide ranges of inborn and acquired brain pathological conditions, such as mitochondrial respiratory chain disorders (MRCD), traumatic brain injury (TBI), sepsis, stroke, neurodegenerative diseases, childhood-onset epileptic encephalopathy, and psychiatric disorders. Therefore, mitochondria are emerging as promising therapeutic targets for brain injury and disorders. However, no non-invasive method is available that can probe in vivo mitochondrial functions in the intact brain in a spatially specific manner. Consequently, there is a lack of effective means for clinical diagnosis and surrogate endpoints for testing therapeutic efficacy. We therefore propose to develop, characterize, and validate a 4D fMRI methodology that can non-invasively probe brain mitochondrial functions. We have established a novel non-invasive 4D functional MRI (4D-fMRI) that can simultaneously capture anatomical and functional features in the same single scan with both high-spatial (isotropic (78µm)3) and temporal resolution (frame rate: ~14 msec). We developed a 4D fMRI protocol dubbed 4D Oxy-wavelet MRI that can probe mitochondrial functions in the intact brains. We have repeatedly observed a strong correlation between the Oxy-wavelet MRI signal and mitochondrial function measured with Oroboros respirometry with brain lysates. Our current goal is to advance this method as a biomarker of mitochondrial function through extensive, rigorous testing in preclinical models of mitochondrial disease with two aims: Specific Aim 1: Definitively establish Oxy-wavelet MRI as an in vivo biomarker of mitochondrial function. We will use drugs to reduce or increase mitochondrial functions to test if 4D Oxy-wavelet MRI can detect the signal changes. In addition, we will manipulate blood flow in the brain. Specific Aim 2: Test the ability of Oxy-wavelet MRI to non-invasively diagnose mitochondrial disease. The objective of this aim is to demonstrate the predictive/diagnostic capability of Oxy-wavelet MRI to diagnose inherited MRCD in the brain as well as acquired mitochondrial dysfunction caused by TBI. Genetically engineered mice with inborn mitochondrial functions as well as mice with blast brain injury will be given to blinded experiments unaware of the mouse identify to make diagnosis of mitochondrial functions based on the 4D Oxy-wavelet results. Impact: This project will pave the way for using MRI to diagnose and manage a host of mitochondrial diseases. In the short term, our study will unequivocally establish and validate 4D Oxy-wavelet MRI as a non-invasive biomarker for detecting mitochondrial dysfunctions in intact brains, both in fetal and adult brains. Our study will also provide new knowledge on how the 4D Oxy-wavelet MRI signals respond to higher electron transport chain activity (mitochondrial uncoupler DNP), depressed mitochondrial function
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210221
Entities
People
- Yijen Wu
Organizations
- United States Army
- University of Pittsburgh