Metabolome analysis using cerebrospinal fluid from narcolepsy type 1 patients

Author:

Shimada Mihoko12,Miyagawa Taku12,Kodama Tohru1,Toyoda Hiromi2,Tokunaga Katsushi23,Honda Makoto14

Affiliation:

1. Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

2. Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

3. Genome Medical Science Project (Toyama), National Center for Global Health and Medicine (NCGM), Tokyo, Japan

4. Seiwa Hospital, Institute of Neuropsychiatry, Tokyo, Japan

Abstract

Abstract Narcolepsy type 1 (NT1) is a hypersomnia characterized by excessive daytime sleepiness and cataplexy. Inappropriate regulation of fatty acid metabolism has been suggested to be involved in the pathophysiology of NT1, but the detailed mechanisms remain uncertain. Here we performed a metabolomic analysis of cerebrospinal fluid samples from 14 NT1 and 17 control subjects using a novel capillary electrophoresis coupled with Fourier transform mass spectrometry. A total of 268 metabolites were identified and the amount of histidine was the most significantly increased in NT1 patients (p = 4.0 × 10–4). Validation analysis using high-performance liquid chromatography (HPLC) including independent replication samples also identified the association of histidine (p = 2.02 × 10–3). Further, levels of histamine, which is synthesized from histidine, were also examined using HPLC and were found to be significantly decreased in NT1 patients (p = 6.12 × 10–4). Pathway analysis with nominally significant metabolites identified several pathways related to the metabolism of glycogenic amino acids, suggesting that glycogenesis is enhanced in NT1 as a compensatory mechanism for fatty acid metabolism. We performed further exploratory analysis, searching for metabolites associated with sleep variables from polysomnography and the multiple sleep latency test. As a result, 5′-deoxy-5′-methylthioadenosine showed a significant association with apnea–hypopnea index (p = 2.66 ×10–6). Moreover, gamma aminobutyric acid displayed a negative correlation with rapid eye movement sleep latency (REML), and thus might represent an intriguing target for future studies to elucidate how the controlling circuit of REM sleep is associated with abnormally short REML in NT1.

Funder

Ministry of Education, Culture, Sports, Science and Technology

Publisher

Oxford University Press (OUP)

Subject

Physiology (medical),Neurology (clinical)

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