160 Chapter 6 Abstract Objective Narcolepsy type 1 (NT1) is a debilitating neurological disorder marked by hypocretin deficiency (or orexin), causing excessive daytime sleepiness and cataplexy. Brain imaging studies have suggested global white matter irregularities (axonal and/or myelin) in NT1, especially in the midbrain, corpus callosum and diffusely in the cortex. Consistent with expected hypocretin projection patterns, the cerebellum was least affected. We examined white matter integrity (axonal and myelin integrity) in NT1 through human postmortem immunohistochemical microscopy. Methods Brain sections from four NT1 donors and ten controls were assessed for axonal density (Bielschowsky silver staining, through axon count and staining intensity), possible axonal injury (SMI312 staining, through area percentage immunoreactivity) and myelin integrity (proteolipid protein and luxol fast blue stainings, through staining intensity). Regions of interest included midbrain subregions, corpus callosum, anterior cingulate, occipital cortex, and as a control region, the cerebellum. Results Axonal density was significantly reduced in NT1 compared to controls in the reticular formation, pyramidal tract, corpus callosum and anterior cingulate gyrus. No significantly different axonal density was seen in the cerebellum nor in the axonal staining colour intensity, axonal injury and myelin integrity measures in any of the regions, except for lower myelin density in NT1 in the secondary visual cortex. Interpretation In NT1, there is widespread lower axonal density within and outside the ascending reticular activating system. The alterations align with typical hypocretin projection patterns and prior in-vivo brain imaging reports, and may contribute to the pathophysiology of NT1, possibly stemming from hypocretin deficiency and/or chronic sleep-wake alterations.
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