In the later stages of HIV infection, patients suffer motor and cognitive problems known as the AIDS dementia complex (ADC). Autopsy reports in HIV patients reveal areas of diffuse myelin pallor and astrocytosis. This injury is somewhat unique in that neurons and astrocytes are usually not infected with the virus despite their participation in the pathology. Therefor, we have begun to look at indirect mechanisms for this injuries. Our working hypothesis is that HIV-related proteins alter the function of glial cells in the brain such that there is a release of more HIV proteins as well as cytokines. These proteins and cytokines then increase Na+/H+ exchange in the astrocyte resulting in an increase in intracellular pH (pHi), outward K+ conductance, and a decrease in glutamate influx. The increase in extracellular K+ and glutamate would result in the excitotoxicity of the surrounding neuros. In a healthy individual, astrocytes play a major role in the homeostatic mechanisms of the brain by regulating ion transport and regulation. Previous experiments in the primary rat astrocytes demonstrate that with a challenge of gp120, an envelope glycoprotein of HIV, there is an amiloride-sensitive intracellular alkalinization and an increase in a pH sensitive K+ channel conductance. In the human astrocyte, we see the increase in K+ conductance and a decrease in the uptake of the neurotransmitter glutamate. We would propose that this alteration in astrocyte activity would then be responsible for pathophysiology of ADC. ?The importance of this study can only be fully appreciated if our hypothesis is investigated in an intact system. Therefore, we have begun to look at pH in the brains of HIV patients. The pH is determined by the chemical shift of inorganic phosphate (Pi) vs. phosphocreatine (PCr) of the 31P NMR spectra acquired in human brains using NMR spectroscopic imaging at the field of 4.1T. Our preliminary studies of asymptomatic HIV+ patients show some of the 9 patients have a slightly increase in pH within the cerebellum. Further studies need to be done on this small pH changes and to look at the metabolite concentration of these patients with stringent statistical analysis. We are proposing to have these patients undergo a series of neuropsychological evaluation to correlate these changes in pH to a measured dementia state.
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