Multiple sclerosis (MS) is one of the most devastating neurological diseases that afflict humans and is marked by variable evolution, neurological disability, and effectiveness of treatments. While it is often impaired motor function (e.g., walking or standing) that receives significant attention in MS literature, cognitive deficits can be equally devastating to day-to-day life. Magnetic resonance imaging (MRI) has been a key radiological imaging method for diagnosing and monitoring treatment in MS, but has suffered when attempting to detect lesions that may occur in the gray matter (GM) of the brain that is directly linked to cognitive impairment in MS. The reason for this is that the majority of MRI methods rely on the amount of water present in a tissue to make images. But, what happens when lesions are present but do not cause the water content to increase (lack of inflammation)? Or, how do we gain information from molecules that are not water, for example, the myelin sheath that surrounds the axons? The former and the latter questions are intimately connected in MS and are perhaps the root of MRI's insensitivity to GM damage.

However, MRI is a flexible imaging modality in that it can derive information from a variety of sources, and two techniques called magnetization transfer (MT) and chemical exchange saturation transfer (CEST) have been recently developed to be sensitive to myelin content (MT) and protein concentration, or neurochemicals (CEST). Importantly, MT and CEST imaging can gain access to tissue changes even when inflammation is not present, making them well suited to the study of GM. However, they have not been routinely studied in the GM because (1) GM is small relative to white matter, (2) they have long acquisition times, and (3) they generally have poor resolution. Current clinical MRI scanners operate at field strengths of 3 Tesla, but research-dedicated scanners can operate at 7 Tesla and above. The advantage of higher field strength magnets is that with increasing field strength, comes an increase in the signal available for imaging that can be translated directly into either faster speed or higher resolution. A further advantage of 7 Tesla is that the underlying biophysics for quantitative MRI methods such as MT and CEST are actually enhanced.

The key problem to be addressed with this proposal is that GM lesions in patients with MS can be directly related to cognitive impairment, yet conventional MRI rarely can detect these lesions. Therefore, a strict relationship between GM tissue damage and cognitive decline has been lacking. We propose that with the advanced methods we have developed at 7 Tesla, we can detect and quantify the effects that result from changes in the myelin content, the accumulation of proteins that may occur prior to lesion formation, and the alteration in the neurochemicals that are responsible for cognitive function in the GM of patients with MS.

Innovative Aspect: MT and CEST imaging have been available for over 20 years. The former has been profoundly studied in MS populations, the latter has only recently gained attention for human application, and only one current publication exists demonstrating CEST MRI in MS. The most innovative aspect of this proposal is not only the usage of 7 Tesla for high-resolution imaging of metabolites, myelin concentration, and neurochemical aberrations, but the combined application of CEST and MT, which may provide a complete picture of lesion burden on GM of patients with MS and cognitive impairment. The development of these techniques for the detailed study of GM is the primary innovation.

Impact on the Field of MS Research/Patient Community: Current MRI methods have poor sensitivity for GM lesions, yet we propose to develop metabolic and macromolecular-sensitive, high-resolution MRI methods to detect and characterize the subtle changes that may occur in GM in patients with MS. While our hypothesis is that with optimization, these techniques can detect and quantify macromolecular and molecular aberrations present in GM offering earlier insight into the evolution of GM disease in patients with MS, the impact to the scientific and MS community is much further reaching. In fact, GM damage in numerous diseases is not trivial to detect. We propose that the immediate impact to MS patients is to offer metabolic biomarkers for disease evolution and evaluation of therapeutic intervention, yet the ability to provide biomarkers for all diseases that directly impact cognitive performance is paramount. If 100% successful, we will have developed for the first time a toolbox to assess the macromolecular, metabolic, and neurochemical profile in the GM of the brain.