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To investigate the source of significant difference in apparent diffusion coefficient (ADC) between patients with acute symptoms of neuropsychiatric (NP) systematic lupus erythematosus (SLE) (NPSLE) and normal controls.Diffusion-weighted echo-planar imaging was performed on 1.5-T scanners in 17 female and four male NPSLE patients with acute neurological symptoms (23–76 years, mean = 42.7 years), and in 21 aged-matched healthy controls (16 female, five male, 26–63 years, mean = 41.1 years). ADC histograms were calculated for whole brain, gray matter tissue, and white matter tissue.Of the 17 NPSLE patients, 13 (72%) had abnormal findings on MR imaging. The NPSLE patients had a mean ADC value of (1105.1 ± 23.6) × 10—6 mm2/second and the control had a mean ADC value of (1012.5 ± 9.4) × 10−6 mm2/second (P ≤ 0.0012). Significant differences were also found in white matter (P ≤ 0.0020) and gray matter (P ≤ 0.0022).ADC histogram analysis demonstrated increased general diffusivity in the brain in NPSLE patients with acute symptoms compared with healthy normal controls. This finding suggests that in the brain parenchyma of NPSLE patients a loss of tissue integrity occurs facilitating motility of free-water protons.