Julien Hédou1, Katie L Cederberg1, Aditya Ambati1, Ling Lin1, Neal Farber2, Yves Dauvilliers3,4, Mohammed Quadri5, Patrice Bourgin6, Giuseppe Plazzi7, Olivier Andlauer8, Seung-Chul Hong9, Yu-Shu Huang10, Smaranda Leu-Semenescu11, Isabelle Arnulf11,12, Shahrad Taheri13, Emmanuel Mignot1. 1. Department of Psychiatry and Behavioral Sciences, Center for Sleep Sciences and Medicine, Stanford University, Palo Alto, CA, USA. 2. Kleine-Levin Syndrome Foundation, Boston, MA, USA. 3. National Reference Centre for Orphan Diseases, Narcolepsy-Rare Hypersomnias, Sleep Unit, Department of Neurology, CHU Montpellier, Univ Montpellier, Montpellier, France. 4. Department of Neurology, Institute for Neurosciences of Montpellier INM, Univ Montpellier, INSERM, Montpellier, France. 5. Hackensack University Medical Center, Hackensack, NJ, USA. 6. Sleep Disorders Center, Hôpitaux Universitaires de Strasbourg, Strasbourg, France. 7. Department of Biomedical and Neuromotor Sciences, University of Bologna and IRCCS Institute of Neurological Sciences, Bologna, Italy. 8. Heads UP Service, East London NHS Foundation Trust, London, UK. 9. Department of Psychiatry, St. Vincent's Hospital, Catholic University of Korea, Seoul, South Korea. 10. Department of Child Psychiatry and Sleep Center, Chang Gung Memorial Hospital and University, Taoyuan, Taiwan. 11. Sleep Disorders, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris-Sorbonne, National Reference Center for Narcolepsy, Idiopathic Hypersomnia and Kleine-Levin Syndrome, Paris, France. 12. Sorbonne University, Institut Hospitalo-Universitaire, Institut du Cerveau et de la Moelle, Paris, France. 13. Department of Medicine and Clinical Research Core, Weill Cornell Medicine-Qatar, Qatar Foundation-Education City, Doha, Qatar.
Abstract
STUDY OBJECTIVES: Kleine-Levin syndrome (KLS) is characterized by relapsing-remitting episodes of hypersomnia, cognitive impairment, and behavioral disturbances. We quantified cerebrospinal fluid (CSF) and serum proteins in KLS cases and controls. METHODS: SomaScan was used to profile 1133 CSF proteins in 30 KLS cases and 134 controls, while 1109 serum proteins were profiled in serum from 26 cases and 65 controls. CSF and serum proteins were both measured in seven cases. Univariate and multivariate analyses were used to find differentially expressed proteins (DEPs). Pathway and tissue enrichment analyses (TEAs) were performed on DEPs. RESULTS: Univariate analyses found 28 and 141 proteins differentially expressed in CSF and serum, respectively (false discovery rate <0.1%). Upregulated CSF proteins included IL-34, IL-27, TGF-b, IGF-1, and osteonectin, while DKK4 and vWF were downregulated. Pathway analyses revealed microglial alterations and disrupted blood-brain barrier permeability. Serum profiles show upregulation of Src-family kinases (SFKs), proteins implicated in cellular growth, motility, and activation. TEA analysis of up- and downregulated proteins revealed changes in brain proteins (p < 6 × 10-5), notably from the pons, medulla, and midbrain. A multivariate machine-learning classifier performed robustly, achieving a receiver operating curve area under the curve of 0.90 (95% confidence interval [CI] = 0.78-1.0, p = 0.0006) in CSF and 1.0 (95% CI = 1.0-1.0, p = 0.0002) in serum in validation cohorts, with some commonality across tissues, as the model trained on serum sample also discriminated CSF samples of controls versus KLS cases. CONCLUSIONS: Our study identifies proteomic KLS biomarkers with diagnostic potential and provides insight into biological mechanisms that will guide future research in KLS.
STUDY OBJECTIVES: Kleine-Levin syndrome (KLS) is characterized by relapsing-remitting episodes of hypersomnia, cognitive impairment, and behavioral disturbances. We quantified cerebrospinal fluid (CSF) and serum proteins in KLS cases and controls. METHODS: SomaScan was used to profile 1133 CSF proteins in 30 KLS cases and 134 controls, while 1109 serum proteins were profiled in serum from 26 cases and 65 controls. CSF and serum proteins were both measured in seven cases. Univariate and multivariate analyses were used to find differentially expressed proteins (DEPs). Pathway and tissue enrichment analyses (TEAs) were performed on DEPs. RESULTS: Univariate analyses found 28 and 141 proteins differentially expressed in CSF and serum, respectively (false discovery rate <0.1%). Upregulated CSF proteins included IL-34, IL-27, TGF-b, IGF-1, and osteonectin, while DKK4 and vWF were downregulated. Pathway analyses revealed microglial alterations and disrupted blood-brain barrier permeability. Serum profiles show upregulation of Src-family kinases (SFKs), proteins implicated in cellular growth, motility, and activation. TEA analysis of up- and downregulated proteins revealed changes in brain proteins (p < 6 × 10-5), notably from the pons, medulla, and midbrain. A multivariate machine-learning classifier performed robustly, achieving a receiver operating curve area under the curve of 0.90 (95% confidence interval [CI] = 0.78-1.0, p = 0.0006) in CSF and 1.0 (95% CI = 1.0-1.0, p = 0.0002) in serum in validation cohorts, with some commonality across tissues, as the model trained on serum sample also discriminated CSF samples of controls versus KLS cases. CONCLUSIONS: Our study identifies proteomic KLS biomarkers with diagnostic potential and provides insight into biological mechanisms that will guide future research in KLS.
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