CP #9: Brain Oxygen Metabolism and Hemodynamic Impairment in Multiple Sclerosis

Significance:

Multiple Sclerosis (MS), a chronic inflammatory disorder of the central nervous system, is the most common cause of nontraumatic disability among young and middle-aged people. Inflammation causes demyelination, which is followed by progressive neurodegeneration. While the mechanism leading from neuroinflammation to neurodegeneration is unknown, recent studies have suggested that the increase of nitric oxide (NO) caused by neuronal/axonal injuries may play a critical role [1-5]. NO competitively inhibits O₂ from binding to the mitochondrial respiratory complex, affecting ATP synthesis. This inability to utilize readily available O₂ is known as “histotoxic hypoxia” [2,5]. The overproduction of NO not only results in cellular energy failure, but it also has a detrimental effect on brain vascular health.

NO is a strong mediator of neurovascular coupling and is responsible for increasing blood supply during transient neural activation [6,7]. Exposure to tonically high levels of NO may alter endothelial function and desensitize the vascular smooth muscle over time. Consequentially, this desensitizing may decrease cerebral vascular reactivity (CVR), which would limit the blood supply when neurons perform a demanding task.  

Aims:

In this study, we will observe and quantify abnormalities of oxygen delivery and oxygen metabolism longitudinally with T₂-Relaxation-Under-Spin-Tagging (TRUST) MRI (Figure 1, [8-10]) in patients with relapsing-remitting (RR) MS and subsequent advanced stages of secondary progress (SP) MS. With this data, we will determine whether the effects of NO lead to disease pathogenesis and progression in MS. We will also examine the relationship between NO level and tissue physiology in a model situation with high/low nitrate diet.

Approach:

MRI will be used to assess the global abnormalities in patients with early RR and SP in comparison to corresponding age/sex matched normal controls. We will also measure the CVR using inhalation of 5% CO₂ and ASL imaging to observe the nature of the hemodynamic dysfunction in the MS patients. The prognostic value of baseline and short-term (3-6 month) cerebral metabolic rate of oxygen (CMRO₂) and CVR for long-term (3 years) clinical and imaging outcome will be determined.  To observe the relationship between NO and disease pathogenesis, we will manipulate NO levels in healthy volunteers using high vs. low-nitrate diet.

Following initial studies at 3T, an arm of the study will be transferred to 7T, using methods developed in the BTRC.  In later stages of the project, we will combine 3T MR with simultaneous PET to add estimates of glucose metabolism, and to cross-validate our MR measures of blood flow and oxygen metabolism. 

Push-Pull Interaction with TR&D Projects 1, 2, 3:

TR&D#1: To cite the summary statement, “rapid acquisitions proposed in TR&D 1 can improve dynamic tracking of flow and oxygenation changes.”  The TRUST technique [8-10] quantitatively measures venous oxygenation (Yv) in the brain based on the principle that T₂ relaxation time of the blood has a well-known and calibratable relationship with Yv. Thus, the rapid and accurate T₂ measurement approaches of TR&D#1 will be of great benefit.  Meanwhile, acceleration of dynamic ASL will allow us to reduce the duration of the CO₂ inhalation challenge (improving patient comfort and reducing motion), and/or increase the fidelity of the data. 

TR&D#2: This CP will benefit markedly from the increased SNR, spatial resolution, labeling persistence (via increased T₁) and oxygen-dependent T₂ contrast available at 7T.  However, TRUST is challenging at 7T despite the obvious theoretical advantages of ultra-high field, given increased B₁ inhomogeneity and SAR for 180⁰ refocusing pulses.  This CP will push the BTRC to develop RF coils, parallel transmission capabilities, and SAR control procedures that will drastically improve the feasibility of TRUST at higher field.

TR&D#3: In addition to the cross-validation mentioned above and encouraged by reviewers, simultaneous MR and PET acquisitions will allow assessment, using tracers such as 18F-PBR111, of neuroinflammatory activity associated with our NO hypothesis but not detected using conventional gadolinium-enhanced MRI [11].