180 Chapter 6 Parkinson’s disease, and Alzheimer’s disease [270]. Given the narcolepsy type 1 chronicity in our sample (with over 40 years of disease duration), it seems logical that no significant SMI312 differences were observed. The specific axonal density changes are also in keeping with DTI validation studies that revealed that lower axonal density in absence of myelin density differences typically results in lower fractional anisotropy with unchanged mean diffusivity (in line with most narcolepsy type 1 DTI studies) [213, 271]. Limitations The most important limitation of this work is the low number of cases. Central disorders of hypersomnolence are rare disorders and only few postmortem brains are available in brain banks across the world. We included four typical narcolepsy type 1 donors. These individuals were clinically well-defined and three showed immunohistochemically confirmed reduced hypocretin cell counts and increased histaminergic neurons as reported in other studies [250, 251]. We observed similar outcomes in our sensitivity analyses when excluding the narcolepsy type 1 donor that had used opiates and a hypocretin level of 200 pg/mL (Appendix A, Supplementary Tables 3-5). Most donors were using medication when passing (such as modafinil and sodium oxybate), which could have influenced white matter morphology. Using the relative colour intensity as an outcome measure is another limitation to the study. This outcome measure was calculated as a ratio using the 95% most intense pixel within the section as a reference value. This was necessary because the overall colour intensity differs between batches in which the sections were processed and thus the absolute colour intensity measures for the regions of interest could not be directly compared. We aimed to conduct other more reliable analyses where possible (manual axon count and automated pixel classification) to deal with this limitation optimally. Conclusion Our immunohistochemic exploration of white matter morphology in narcolepsy type 1 revealed intriguing insights into its structural complexities. We show widespread axonal loss within the ascending reticular activating system, pyramidal tract, corpus callosum and anterior cingulate gyrus, while the cerebellum remains relatively unaffected. These findings align with prior in-vivo DTI reports and typical hypocretin projection patterns, and offer valuable insights into the potential pathophysiological mechanisms underlying narcolepsy type 1, possibly stemming from hypocretin deficiency and/or
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