161 Axonal Loss in Narcolepsy Type 1 Introduction Narcolepsy type 1 is a primary neurological sleep disorder caused by hypocretin (or orexin) deficiency, leading to excessive daytime sleepiness, cataplexy (transient episodes of muscle weakness triggered by emotions). Narcolepsy type 1 arises from an interaction between genetic and environmental triggers that ultimately lead to selective immune-mediated destruction or dysfunction of hypocretin-producing neurons in the lateral hypothalamus [4]. Hypocretin typically has an important modulatory role in adequate sleep-wake control through diffuse cortical connections and dense projections to parts of the ascending reticular activating system (locus coeruleus, dorsal raphe nucleus, tuberomammillary nucleus, ventral tegmental area, paraventricular nucleus and basal forebrain) [38, 237]. The cerebellum is the most prominent brain region that is not directly innervated by hypocretin-producing neurons. Whether hypocretin deficiency in narcolepsy type 1 leads to impaired white brain matter integrity remains unknown. Multiple magnetic resonance imaging (MRI) studies used diffusion tensor imaging (DTI) in narcolepsy type 1 to assess white matter integrity [84, 104-107, 109, 110, 238]. DTI uses directionality and extent of whole brain water diffusion as an indirect measure for structural white matter morphology, particularly myelin and axonal integrity. The DTI studies in narcolepsy type 1 mainly found lower fractional anisotropy and higher radial diffusivity which suggests morphological changes in the direction perpendicular to axon bundles [84, 104-107, 109, 110, 238], possibly related to larger axonal diameters, lower axonal density, decreased myelination or a combination of these factors [210, 211]. Practically all regions of the brain were involved except for the cerebellum (for instance, hypothalamus, brainstem, thalamus, hippocampus, amygdala and cortex), which is in line with the widespread projection pattern of hypocretin [208]. These findings have been interpreted as the structural underpinnings for functional alterations in the ascending reticular activating, reward, limbic and motor systems in narcolepsy type 1. The exact neurobiological basis of these DTI differences remains unclear and could be explained by axonal and/or myelin differences, or other factors that influence cerebral water diffusion [104]. Histopathological analyses using postmortem human brain tissue are best suited to investigate potential microstructural white matter disruptions and such studies have not yet been performed in narcolepsy type 1. White matter morphology is generally assessed using combined axonal and myelin stainings. The Bielschowsky silver staining can be used as an axonal marker due to the high affinity for silver of axons, giving the opportunity to trail individual axons 6
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