White and gray matter abnormalities in narcolepsy with cataplexy.

Study Objectives: The authors applied diffusion-tensor imaging including measurements of mean diffusivity (MD), which is a parameter of brain tissue integrity, fractional anisotropy (FA), which is a parameter of neuronal fiber integrity, and voxel-based morphometry, which is a measure of gray and white matter volume, to detect brain tissue changes in patients with narcolepsy-cataplexy. Design: N/A. Patients: Patients with narcolepsy-cataplexy (n = 16) and age-matched healthy control subjects (n = 12) were studied. Interventions: Whole cerebral MD, FA measures, and the volumes of the gray and white matter compartments were analyzed using statistical parametric mapping. Measurement and Results: Significant MD increases and concomitant FA decreases were localized in the fronto-orbital cortex (P < 0.001) and the anterior cingulate (FA, P < 0.001; MD, P = 0.03) in narcolepsy-cataplexy. Additional MD increases without FA changes were detected in the ventral tegmental area, the dorsal raphe nuclei (P < 0.001), and the hypothalamus (P < 0.01). FA signal decreases were observed in the white matter tracts of the inferior frontal and inferior temporal cortices of narcolepsy-cataplexy patients (P < 0.001). Brain volume loss was evident in focal areas of the inferior and superior temporal cortices (P < 0.001) and the cingulate (P = 0.038). Conclusions: Areas of increased diffusivity in the hypothalamus appear consistent with hypocretinergic cell loss reported in narcolepsy-cataplexy. Signal abnormalities in the ventral tegmental area and the dorsal raphe nuclei correspond to major synaptic targets of hypocretin neurons that were associated with the regulation of the sleep-wake cycle. Brain tissue alterations identified in the frontal cortex and cingulate are crucial in the maintenance of attention and reward-dependent decision making, both known to be impaired in narcolepsy-cataplexy.