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OBJECTIVE: To determine the histopathologic basis of altered brain neurometabolites in neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: Brain neurometabolite concentrations in a 20-voxel area of the brain were determined premortem by magnetic resonance spectroscopy (MRS) in 7 individuals with NPSLE. Absolute concentrations of neurometabolite for N-acetylaspartate (NAA), choline, creatine, and lactate were measured. After the death of the patients, histopathologic changes were determined at autopsy of the brain and were matched voxel-by-voxel with the neurometabolites. RESULTS: The mean +/- SD absolute concentrations of NAA (9.15 +/- 1.78 mM in patients versus 12.2 +/- 0.8 mM in controls; P < 0.01) and creatine (6.43 +/- 0.16 mM in patients versus 6.90 +/- 0.60 mM in controls; P < 0.003) were significantly reduced and the concentration of choline (2.51 +/- 0.42 mM in patients versus 1.92 +/- 0.32 mM in controls; P < 0.04) was significantly elevated in NPSLE patients as compared with controls. Widespread heterogeneous changes in the histologic features of the brain were present, including microinfarcts, microhemorrhages, bland angiopathy, thrombotic angiopathy with platelet and fibrin thrombi, neuronal necrosis in various states of resolution, reduced numbers of axons and neurons, vacuole and space formation among the fibers, reduced numbers of oligodendrocytes, reactive microglia and astrocytes, lipid-laden macrophages, and cyst formation. Neurometabolite abnormalities were closely associated with underlying histopathologic changes in the brain: 1) elevated choline levels were independently associated with gliosis, vasculopathy, and edema (r = 0.75, P < 0.004 in the multivariate model); 2) reduced creatine levels with reduced neuronal-axonal density and gliosis (r = 0.72, P < 0.002 in the multivariate model); 3) reduced NAA levels with reduced neuronal-axonal density (r = 0.66, P < 0.001 in the multivariate model); and 4) the presence of lactate with necrosis, microhemorrhages, and edema (r = 0.996, P < 0.0001 in the multivariate model). CONCLUSION: Altered neurometabolites in NPSLE patients, as determined by MRS, are a grave prognostic sign, indicating serious underlying histologic brain injury. [ABSTRACT FROM AUTHOR]