Microglia Density and Its Association With Disease Duration, Severity, and Orexin Levels in Patients With Narcolepsy
Lucie Barateau1, Anis Krache1, Alexandre Da Costa1
1From the Sleep-Wake Disorders Unit (L.B., S.C., Y.D.), Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier; National Reference Centre for Orphan Diseases (L.B., Y.D.), Narcolepsy, Idiopathic Hypersomnia, and Kleine-Levin Syndrome, Montpellier; Institute of Neurosciences of Montpellier (L.B., S.B., I.J., Y.D.), University of Montpellier, INSERM; ToNIC (A.K., A.D.C., A.-S.S., S.S., P.P.), Toulouse NeuroImaging Center, UMR 1214, INSERM, Université Paul-Sabatier, Toulouse; Pediatric Sleep Centre (M.L.), Hospital Robert-Debré; National Reference Centre for Orphan Diseases, Narcolepsy, Idiopathic Hypersomnia, and Kleine-Levin Syndrome (M.L.), Paris; Sleep Unit of Toulouse Hospital (R.D.), National Competence Centre for Orphan Diseases, Narcolepsy, Idiopathic Hypersomnia, and Kleine-Levin Syndrome, Department of Neurology; CHRU de Tours-Université de Tours (N.A., P.V.), Inserm U1253 « Imaging and Brain » (iBrain), Inserm CIC 1415, Tours; Sleep Unit (E.E.), CHU Nîmes; Radiopharmacy Department (M.A., A.-S.S.), CHU Toulouse; Critical Care Unit (S.S.), Purpan University Hospital, Toulouse; Department of Nuclear Medicine (D.M.-G.), CHU Montpellier; PhyMedExp (D.M.-G.), University of Montpellier, INSERM, CNRS; and Nuclear Medicine Department (P.P.), CHU Toulouse, France.
Background And Objectives:
Narcolepsy type 1 (NT1) is due to the loss of hypothalamic neurons that produce orexin (ORX), by a suspected immune-mediated process. Rare postmortem studies are available and failed to detect any inflammation in the hypothalamic region, but these brains were collected years after the first symptoms. In vivo studies close to disease onset are lacking. We aimed to explore microglia density in the hypothalamus and thalamus in NT1 compared with controls using [18F]DPA-714 PET and to study in NT1 the relationships between microglia density in the hypothalamus and in other regions of interest (ROIs) with disease duration, severity, and ORX levels.
Methods:
Patients with NT1 and controls underwent a standardized clinical evaluation and [18F]DPA-714 PET imaging using a radiolabeled ligand specific to the 18 kDa translocator protein (TSPO). TSPO genotyping determined receptor affinity. Images were processed on peripheral module interface using standard uptake value (SUV) on ROIs: hypothalamus, thalamus, frontal area, cerebellum, and the whole brain. SUV ratios (SUVr) were calculated by normalizing SUV with cerebellum uptake.
Results:
A total of 41 patients with NT1 (21 adults, 20 children, 10 with recent disease onset <1 year) and 35 controls were included, with no significant difference between groups for [18F]DPA-714 binding (SUV/SUVr) in the hypothalamus and thalamus. Unexpectedly, significantly lower SUVr in the whole brain was found in NT1 compared with controls (0.97 ± 0.06 vs 1.08 ± 0.22, p = 0.04). The same finding between NT1 and controls in the whole brain was observed in those with high or mixed TSPO affinity (p = 0.03 and p = 0.04). Similar trend was observed in the frontal area in NT1 (0.96 ± 0.09 vs 1.09 ± 0.25, p = 0.05). In NT1, no association was found between SUVr in different ROIs and age, disease duration, severity, or ORX levels.
Discussion:
We found no evidence of in vivo increased microglia density in NT1 compared with controls, even close to disease onset, and even unexpectedly a decrease in the whole brain of these patients. These findings do not support the presence of neuroinflammation in the destruction process of ORX neurons.
Trial Registration Information:
ClinicalTrials.org NCT03754348.
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