Keita Takahashi1, Yuji Kurihara2, Yume Suzuki3, Yoshio Goshima4, Fumiaki Tanaka3, Kohtaro Takei2. 1. Molecular Medical Bioscience Laboratory, Department of Medical Life Science, Yokohama City University Graduate School of Medical Life Science, Yokohama, Japan2Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicin. 2. Molecular Medical Bioscience Laboratory, Department of Medical Life Science, Yokohama City University Graduate School of Medical Life Science, Yokohama, Japan. 3. Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan. 4. Department of Molecular Pharmacology and Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Abstract
IMPORTANCE: Although multiple sclerosis (MS) is generally considered an autoimmune demyelinating disorder of the central nervous system, axonal degeneration through Nogo receptor-1 signaling was recently recognized as an important pathological feature. Our previous identification of lateral olfactory tract usher substance (LOTUS), an endogenous Nogo receptor-1 antagonist, prompted us to analyze the relationship between LOTUS levels of cerebrospinal fluid and the clinical course of MS to evaluate whether LOTUS could be a useful biomarker for MS. OBJECTIVE: To examine variations in LOTUS concentrations in the cerebrospinal fluid of patients with MS in accordance with their clinical course. DESIGN, SETTING, AND PARTICIPANTS: Cerebrospinal fluid samples were obtained retrospectively from normal controls (NCs; n = 27) and patients with MS (n = 40), amyotrophic lateral sclerosis (n = 22), and multiple system atrophy (n = 10) between January 1, 2008, and January 1, 2014. Patients with MS were divided into relapsing-remitting MS (RRMS; n = 30) and secondary progressive MS (n = 10). Patients with RRMS were further divided into relapse and remission groups. MAIN OUTCOMES AND MEASURES: The LOTUS concentration in cerebropsinal fluid was quantitatively detected by immunoblotting using a specific LOTUS antibody and the concentrations compared in accordance with the patients' clinical course, such as remission and relapse groups in RRMS and secondary progressive MS. RESULTS: The mean (SD) cerebrospinal fluid LOTUS concentration in the relapse group of RRMS (9.3 [3.6] µg/dL) was lower than that of NCs (19.2 [4.7] µg/dL; P < .001) whereas the level in the remission group of RRMS (19.6 [5.8] µg/dL) was similar to that of NCs. The LOTUS concentration in SPMS (6.7 [1.4] µg/dL; P < .001) was lower than that of NCs and the remission group of RRMS. The LOTUS levels in other neurodegenerative diseases, such as amyotrophic lateral sclerosis and multiple system atrophy, were normal. CONCLUSIONS AND RELEVANCE: Variations in LOTUS concentrations were correlated with disease activity in MS. Therefore, LOTUS concentration may be useful as a possible biomarker for MS. Low LOTUS concentrations may be possibly involved in Nogo receptor-1 signaling, which may induce axonal degeneration in the relapse phase of RRMS and secondary progressive MS.
IMPORTANCE: Although multiple sclerosis (MS) is generally considered an autoimmune demyelinating disorder of the central nervous system, axonal degeneration through Nogo receptor-1 signaling was recently recognized as an important pathological feature. Our previous identification of lateral olfactory tract usher substance (LOTUS), an endogenous Nogo receptor-1 antagonist, prompted us to analyze the relationship between LOTUS levels of cerebrospinal fluid and the clinical course of MS to evaluate whether LOTUS could be a useful biomarker for MS. OBJECTIVE: To examine variations in LOTUS concentrations in the cerebrospinal fluid of patients with MS in accordance with their clinical course. DESIGN, SETTING, AND PARTICIPANTS: Cerebrospinal fluid samples were obtained retrospectively from normal controls (NCs; n = 27) and patients with MS (n = 40), amyotrophic lateral sclerosis (n = 22), and multiple system atrophy (n = 10) between January 1, 2008, and January 1, 2014. Patients with MS were divided into relapsing-remitting MS (RRMS; n = 30) and secondary progressive MS (n = 10). Patients with RRMS were further divided into relapse and remission groups. MAIN OUTCOMES AND MEASURES: The LOTUS concentration in cerebropsinal fluid was quantitatively detected by immunoblotting using a specific LOTUS antibody and the concentrations compared in accordance with the patients' clinical course, such as remission and relapse groups in RRMS and secondary progressive MS. RESULTS: The mean (SD) cerebrospinal fluid LOTUS concentration in the relapse group of RRMS (9.3 [3.6] µg/dL) was lower than that of NCs (19.2 [4.7] µg/dL; P < .001) whereas the level in the remission group of RRMS (19.6 [5.8] µg/dL) was similar to that of NCs. The LOTUS concentration in SPMS (6.7 [1.4] µg/dL; P < .001) was lower than that of NCs and the remission group of RRMS. The LOTUS levels in other neurodegenerative diseases, such as amyotrophic lateral sclerosis and multiple system atrophy, were normal. CONCLUSIONS AND RELEVANCE: Variations in LOTUS concentrations were correlated with disease activity in MS. Therefore, LOTUS concentration may be useful as a possible biomarker for MS. Low LOTUS concentrations may be possibly involved in Nogo receptor-1 signaling, which may induce axonal degeneration in the relapse phase of RRMS and secondary progressive MS.