Introduction

Narcolepsy type 1 (NT1) is a rare sleep disorder characterized by excessive daytime sleepiness and cataplexy, probably linked to the loss of orexin-producing neurons in the hypothalamus; the latter has connections to various brain regions, including the thalamus, which acts as a hub also for sleep-wake regulation. Advanced neuroimaging like quantitative susceptibility-mapping (QSM) can show magnetic susceptibility alterations representing iron overload as neurodegenerative effect.

Methods

81 NT1 patients (36M, 34.7±13.5yo) and 59 healthy controls (34M, 38.8±13.2yo) underwent 3T-MRI protocol including T1-weighted MPRAGE and QSM sequences. Thalamic nuclei were segmented from T1-weighted images using an atlas-based method¹, registered to QSM, and their magnetic susceptibility (χ) values were extracted. Raw data were corrected for age using linear regression based on the control group. Normality was assessed using the Shapiro-Wilk test, and statistical comparisons were performed using ANOVA or the Mann-Whitney U test, with corrections for multiple comparisons.

Results

Significant increase in χ-value was found in whole thalamus (p=0.01) and several subnuclei, namely: lateral-geniculate (p=0.02), medial-geniculate (p=0.04), lateral (p=0.08), medial (p=0.02), lateral-posterior (p=0.009), anterior-pulvinar (p=0.05), centromedian (p=0.008), central-lateral (p=0.009), and pulvinar (p=0.008).

Conclusions

The results suggest thalamic iron overload²: notable changes occurred in centromedian, central-lateral, median nuclei (connected to reticular formation, regulating wakefulness) and pulvinar (involved in regulating low-frequency waves of sleep). These indicate a broader involvement of brain beyond the hypothalamus in NT1, potentially reflecting a diffuse neurodegenerative process³. QSM, a non-invasive imaging technique, could serve as a valuable tool for defining the pathogenetic mechanisms and monitoring the disease progression in-vivo.

1. Brun et al. Automatic segmentation of deep grey nuclei using a high-resolution 7T magnetic resonance imaging atlas Quantication of T1 values in healthy volunteers. Eur J Neurosci, 2022; 55(2):438–460;

2. Hametner S et al. The influence of brain iron and myelin on magnetic susceptibility and effective transverse relaxation – A biochemical and histological validation study. Neuroimage. 2018 Oct 1;179:117-133. doi: 10.1016/j.neuroimage.2018.06.007. Epub 2018 Jun 15. PMID: 29890327.

3. Nikparast, F. et al. Brain pathological changes during neurodegenerative diseases and their identification methods: How does QSM perform in detecting this process?. Insights Imaging 13, 74 (2022). https://doi.org/10.1186/s13244-022-01207-6