101 Decreased glutamate levels were observed in parallel with NAA in several neurological diseases and disease models,85,102,103 likely because glutamatergic neurons make up

the majority of neurons in the central nervous system (CNS). However, MRS detects both the neurotransmitter and metabolic pools of glutamate and alterations of glutamate levels in the absence of parallel NAA changes are possible.86,104 Most inhibitory neurons in the CNS are GABAergic and have low levels of glutamate In their cell bodies and processes.101 GABA is potentially a good marker for these neurons because GABA concentrations and GABA-like immunoreactivity are highest in these neurons.105,106 Inhibitors,research,lifescience,medical In addition to neuronal markers, MRS enables detection of several putative glial markers: cell culture studies suggested a primarily glial localization for myo-inositol107 and its levels were increased Inhibitors,research,lifescience,medical with gliosis in the monkey and rat

brain.86,108 Therefore, increased myo-inositol levels have often been attributed to gliosis in neurological disorders.102,109-111 However, the glial localization of myoinositol has been disputed112 and its levels do not always correlate with reactive astrogliosis.113 Myo-inositol has multiple functions in cells. For example it plays an essential role in the regulation Inhibitors,research,lifescience,medical of cell volume in CNS as one of the most important organic osmolytes112 and therefore may mark various cellular changes. An alternative glial marker is glutamine, Inhibitors,research,lifescience,medical which can be reliably quantified using high field MRS. Glutamine is preferentially localized in glial cells,100,101

and elevated glutamine levels were detected in diseases in which gliosis is known to occur.102,109 Total creatine (creatine + phosphocreatine, tCr) and OTX015 price Choline-containing compounds (tCho) are also highly concentrated in glial cells114 and therefore may also increase with gliosis. Since both neurons and glia contain creatine and phosphocreatine, tCr has been utilized as a measure of total cellular density and its increase has been interpreted as Inhibitors,research,lifescience,medical glial proliferation that is not counterbalanced by neuroaxonal loss.111,115 Choline-containing compounds, on the other hand, may also become increasingly MR visible with increased membrane turnover or breakdown, such as during active demyelination.109,116 Methisazone Therefore, tCr and tCho changes mayhave multiple implications that need to be determined for each disease in question. In addition to the putative neuronal and glial markers, MRS can provide insights into energetic status and inflammation. For example, changes in the phosphocreatine-to-creatine ratio may be indicative of disturbances in energy metabolism.117,118 Lactate increases can be associated with anaerobic metabolism of infiltrating macrophages or indicate impaired mitochondrial function.