179 Axonal Loss in Narcolepsy Type 1 between the frontal lobes [104, 106, 238]. Motor neurons within the pyramidal tract have been linked to muscle atonia observed during cataplexy episodes [267], and the reduced axonal density within the pyramidal tract could be a sign of further downstream neuronal changes in the spinal cord. When comparing groups, the non-significantly different axon directionality ratios in the anterior cingulate gyrus and corpus callosum indicate that the directionality of the loss of axons within these regions was unselective. Myelin integrity We observed no generalized myelin abnormalities in narcolepsy type 1, consistent with quantitative MRI and DTI studies [105, 106, 238, 258]. This also aligns with the non-progressive nature of narcolepsy type 1, unlike most myelincentred disorders (such as multiple sclerosis). Within our post-hoc analyses, we uncovered reduced myelin in the secondary visual cortex in the PLP staining. Increased activity within higher order visual processing regions was recently found in narcolepsy type 1 when resisting sleep, which was interpreted as an increased need for sensory focus to maintain wakefulness [268]. Slowing of electroencephalography activity in the occipital cortex has also been related to microscleep occurrence in narcolepsy type 1 [269]. The compromised myelin integrity we observed, could underlie the functional occipital changes in narcolepsy type 1. This finding should be carefully interpreted as a similar pattern was not found in the other LFB myelin integrity staining or in other investigated ROIs. Methodological considerations Significant differences in manual axon counting, in contrast to color intensity analysis, were observed in Bielschowsky silver staining. No significant differences were found in our axonal injury staining (SMI312). Understanding these findings requires consideration of intrinsic differences between the stainings and analysis methods. The Bielschowsky silver staining highlights axons through visible silver in neurofibrils, neurofibrillary tangles and neuronal processes [240]. These heavily coloured neuronal components however only partially cover the section and the additional background colouring makes the averaged colour intensity analyses less sensitive to axonal density changes compared to the manual axon counting. SMI312’s phosphorylation of axonal epitopes on neurofilaments M and H may be the key in explaining the different results of the two axonal markers [241, 242]. Accumulation of neurofilament proteins results from axonal stress (related to acute axonal injury) and has been seen in different neurological diseases, such as amyotrophic lateral sclerosis, 6
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