Projects

The brain uses huge amounts of glucose and oxygen relative to its mass and the careful regulation of these metabolic substrates is critically important to maintaining brain function and facilitating repair in the face of disease.

MS may disrupt cerebral metabolism in a number of ways including:

• Loss of myelin increases the metabolic cost of ionic gradients
• Reactive production of metabolically compromised mitochondria
• Increased metabolic demand from infiltrative inflammatory cells
• High metabolic cost of remyelination.

We are interesting in understanding how metabolism of glucose and oxygen are disrupted in MS and how these disruptions impact ongoing clinical progression, response to treatment, and tissue repair. We are using FDG PET to measure cerebral metabolic rate of glucose and oxygen sensitive MRI to measure the cerebral metabolic rate of oxygen.

This work is supported by NIH and Consortium of Multiple Sclerosis Centers.

Relapsing MS is clearly an inflammatory process, and that inflammatory activity is dramatically reduced by available disease modifying therapies. Measuring this impact in the central nervous system is complicated by the blood brain barrier and general inaccessibility of the compartment.

We work with collaborators to bring new radiotracers into human studies in order to ask how immune dysregulation manifests within the brain of MS patients and how this is impacted by treatment. In particular, we are interested in aberrant inflammation that persists despite therapy as this is a candidate driver of continued immune-mediated damage in progressive MS. Specifically, we are developing and validating tracers targeted at specific components of the MS pathological process (e.g., S1P1-signalling) and Bruton’s tyrosine kinase.

This work is in collaboration with the labs of Dr. Tammie Benzinger and Dr. Will Tu. This work is supported by NIH and private philanthropy.

As a consequence of effective disease modifying therapies, patients with MS are now expected to have normal lifespans. A predictable consequence of this incredible advance is that MS patients will begin to experience age-related disease. This is largely true and MS patients are developing diabetes, heart disease, etc. at approximately normal rates. We have observed that MS patients tend to not develop cognitive impairment classic of Alzheimer dementia. We are testing the hypothesis that MS is protective against some neurodegenerative conditions. As a hypothesis, the microglia over-activation characteristic of MS may provide some protection against pathologic protein accumulation.

A second interest related to MS and aging is the co-morbidity of MS and cerebral small-vessel disease. Small-vessel disease is an ischemic process which also causes lesions in the brain which can sometimes be difficult to distinguish from MS lesions. Its important to differentiate these etiologies since new MS lesion formation impacts clinical care.

This work is funded by the Hope Center at Washington University.

Patients with multiple sclerosis undergo MRI evaluation frequently, with most patients getting brain MRIs at least yearly. Thus, there is a huge amount of information already being acquired in each patient. However, clinically, we rely on relatively simple metrics to determine diagnosis, evaluate disease severity, and assess treatment response. We are interested in developing new tools to extract more information from existing clinical MRI scans to improve prognosis or our understanding of MS pathophysiology.