Neurological diseases are a significant and increasing burden on our society. These include
multiple sclerosis (MS), autism, Alzheimer's disease, mild traumatic brain injury etc. Many are
associated with age. These diseases have a high societal impact in terms of cost to patients and the
health system. Damaged mitochondria and oxidative metabolism are often implicated. There are few
methods available to study mitochondrial function in living brain. Since mouse is the main preclinical
model, and oxidative metabolism is high in gray matter (GM), we will develop methods specifically
targeted to the difficult task of studying oxidative metabolism in vivo in mouse cortical gray matter.
This project is to integrate, optimize and show proof of principle for a new multimodel
MRI/near-infrared spectroscopy method for studying oxidative metabolism and mitochondrial
function in gray matter of mouse models of neurological disease. Using a mouse model of
multiple sclerosis for proof of principle, we will gain new knowledge of the relationships
between mitochondrial damage, hypoxia, oxidative metabolism, and demyelination.
In Aim 1, we will integrate and the MRI/NIRS system using geometries appropriate for mouse
brain gray matter. Perfusion will be quantified using MRI; arterial oxygen saturation with a pulse
oximeter; and microvascular oxygen saturation, venous hemoglobin saturation and total hemoglobin
from broadband NIRS (to calculate GM CMRO2) Hemoglobin saturation provides a hypoxia marker.
We will introduce cytochrome oxidase Cua redox data collection to assess mitochondrial redox, model
light penetration in the mouse head to optimize for gray matter, integrate the data collection to one
portable software package and determine reproducibility in a cohort of mice.
In Aim 2, as proof of principle, we will study the cuprizone mouse model of MS. The model is
demyelinating, has damaged mitochondria and hypoxia has been suggested to occur. Current
treatments in MS focus on inflammation and demyelination but axonal loss and atrophy still occur.
There may be a defect in mitochondrial function. We will show how CMRO2, perfusion, hypoxia and
mitochondrial redox status are related to demyelination and symptoms.
We will develop an MRI/NIRS system for assessing oxidative metabolism in gray matter of mouse
models of neurological disease opening up new avenues of research to study the interplay between
mitochondrial damage, oxidative metabolism, perfusion and hypoxia. We will show proof of principle
by obtaining new and novel data showing how oxidative metabolism relates to demyelination in a
mouse model of MS.
