16 Chapter 1 fluctuations in narcolepsy incidence rates. In Chapter 4 we cross-sectionally investigate the self-reported immunological triggers before onset of narcolepsy type 1 and type 2, and idiopathic hypersomnia. The cellular processes induced by a potential immunological trigger that ultimately lead to hypocretin deficiency in narcolepsy type 1 have been extensively studied. Specific CD4+ T-cells targeting hypocretin have been identified in the blood of individuals with narcolepsy type 1 [68, 69] but these findings have not been consistently replicated [70, 71]. In contrast to CD8+ T-cells, such CD4+ T-cells cannot directly have harmed hypocretin neurons, as they only recognize HLA type II molecules on professional antigen-presenting immune cells instead of the HLA type I molecules expressed by neurons [72]. Additional involvement of HLA type II-mediated effector immune cells seems inevitable but this process remains incompletely understood. Postmortem brain tissue microscopy of a donor with secondary narcolepsy type 1 by Ma2 antibody encephalitis showed hypothalamic CD8+ T-cell infiltration, suggesting a role in disease development [73]. Hypocretin-reactive cytokine-producing CD8+ T-cells have been found in blood sera of children with narcolepsy type 1 (but not in adults) [74]. Increased CD8+ T-cell autoreactivity to narcolepsy type 1-related proteins has additionally been reported in narcolepsy type 1 adults compared to HLA DQB1*06:02 positive healthy controls [75]. CD8+ T-cells have therefore been associated with hypocretin deficiency but a causal relationship has yet to be proven. Taken together, the underlying immunological mechanisms of narcolepsy type 1 remain only partially understood. Neuroimaging The discovery of hypocretin deficiency occurred around the same time as the rising use of magnetic resonance imaging (MRI) [44, 45]. MRI has since been widely implemented to investigate narcolepsy type 1 [76]. An improved understanding of brain structure and functioning in central disorders of hypersomnolence could assist in unravelling disease pathophysiology and provide important new targets for disease management strategies. For a full overview of structural and functional MRI, PET and SPECT studies investigating central disorders of hypersomnolence, please see Appendix A. Structural neuroimaging in narcolepsy type 1 Using volumetric analyses to investigate structural differences led several studies to observe volume reductions in the hypothalamus (Figure 1) [77-81], with one of these studies also reporting correlations between these changes
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