This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Pathologic processes affect the concentrations of certain metabolites or neurotransmitters as well as local surroundings such as pH and blood flow. Glycine is a neurotransmitter that serves as an important inhibitory neurotransmitter in the central nervous system. Glycine-dependent synapses are found to be highly concentrated in the brain stem, retina, and spinal cord. The presence and location of glycine receptors suggest that glycine signaling might be a key player in the neural pathology of many motor and cognitive diseases;some notable examples include Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease, hyperekplexia, and paroxysmal movement. Measurement of these factors invasively is difficult and may pose more harm to the patient than benefit. While magnetic resonance spectroscopy (MRS) has previously been used to measure neurotransmitter concentrations in the central nervous system (CNS), this technique lacks the adequate spatial resolution to be used in routine clinical studies. The ability to measure such aspects non-invasively at high resolutions would be a major breakthrough in the diagnoses of these and many other disorders. Chemical exchange between labile protons of proteins and water protons can make Magnetic Resonance Imaging (MRI), utilized mainly for the detection of bulk water signal, sensitive to information about the concentrations of endogenous proteins and their environments. Recently, a technique called Chemical Exchange Dependent Saturation Transfer (CEST), which uses the attenuation of bulk water magnetization through magnetization exchange with saturated labile protons, has been used to characterize properties of dilute labile groups. While CEST studies have explored numerous metabolites, there have been no studies demonstrating the CEST effect in glycine. Spin-lattice relaxation in the rotating frame (T1?) is another contrast technique that depends on chemical exchange. There have been no studies to date using T1? for contrast in the chemical exchange of protons. T1? Chemical exchange effects vary quadratically with the static magnetic field. Therefore, T1? potentially offer higher sensitivity at higher fields in probing exchange mediated interactions in nuclear spin systems. This higher sensitivity of T1? MRI may enable detection of metabolites with very low concentrations (~1 mM) in the brain. We hypothesize that it is possible to quantify the CEST effect in glycine at higher magnetic fields (e3T). Also, that T1? MR imaging has higher sensitivity to proton chemical exchange than the CEST method at ultra-high static fields. Finally, we believe that it is feasible to measure glycine in vivo in the spinal cord. These hypotheses will be tested by accomplishing the following specific aims:
Aim #1 : To measure the chemical shift of glycine in-vitro under physiological conditions using CEST imaging.
Aim #2 : To determine the effect that concentration, pH, static magnetic field, B1 field strength and saturation time have on the chemical exchange of glycine.
Aim #3 : To demonstrate, at varying static magnetic field strengths, that the chemical shift of glycine can provide contrast on T1??weighted images and that at ultra-high static fields it shows greater sensitivity than the CEST effect.
Aim #4 : To measure glycine concentrations non-invasively in-vivo in rat models using CEST and T1??weighted images.
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