Daniel Alcolea1, Pablo Martínez-Lage1, Pascual Sánchez-Juan1, Javier Olazarán1, Carmen Antúnez1, Andrea Izagirre1, Mirian Ecay-Torres1, Ainara Estanga1, Montserrat Clerigué1, Maria Concepción Guisasola1, Domingo Sánchez Ruiz1, Juan Marín Muñoz1, Miguel Calero1, Rafael Blesa1, Jordi Clarimón1, María Carmona-Iragui1, Estrella Morenas-Rodríguez1, Eloy Rodríguez-Rodríguez1, José Luis Vázquez Higuera1, Juan Fortea1, Alberto Lleó2. 1. From the Department of Neurology (D.A., R.B., J.C., M.C.-I., E.M.-R., J.F., A.L.), Institut d'Investigacions Biomèdiques Sant Pau, Hospital de Sant Pau, Universitat Autònoma de Barcelona; Fundación CITA-Alzhéimer Fundazioa (P.M.-L., A.I., M.E.-T., A.E., M.C.), San Sebastián; Servicio de Neurología (P.S.-J., E.R.-R., J.L.V.H.), Hospital Universitario Marqués de Valdecilla, Santander; Servicio de Neurología (J.O., D.S.R.) and Unidad de Medicina Experimental (M.C.G.), Hospital General Gregorio Marañón, Madrid; Unidad de Demencias (C.A., J.M.M.), Hospital Clínico Universitario Virgen de la Arrixaca, Murcia; Instituto de Salud Carlos III (M.C.), CIBERNED, Madrid; Fundación CIEN (J.O., M.C.), Fundación Reina Sofía, Madrid; and Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas, CIBERNED (The SIGNAL Study), Spain. 2. From the Department of Neurology (D.A., R.B., J.C., M.C.-I., E.M.-R., J.F., A.L.), Institut d'Investigacions Biomèdiques Sant Pau, Hospital de Sant Pau, Universitat Autònoma de Barcelona; Fundación CITA-Alzhéimer Fundazioa (P.M.-L., A.I., M.E.-T., A.E., M.C.), San Sebastián; Servicio de Neurología (P.S.-J., E.R.-R., J.L.V.H.), Hospital Universitario Marqués de Valdecilla, Santander; Servicio de Neurología (J.O., D.S.R.) and Unidad de Medicina Experimental (M.C.G.), Hospital General Gregorio Marañón, Madrid; Unidad de Demencias (C.A., J.M.M.), Hospital Clínico Universitario Virgen de la Arrixaca, Murcia; Instituto de Salud Carlos III (M.C.), CIBERNED, Madrid; Fundación CIEN (J.O., M.C.), Fundación Reina Sofía, Madrid; and Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas, CIBERNED (The SIGNAL Study), Spain. alleo@santpau.es.
Abstract
OBJECTIVE: To investigate CSF markers involved in amyloid precursor protein processing, neuronal damage, and neuroinflammation in the preclinical stages of Alzheimer disease (AD) and participants with suspected non-Alzheimer pathology (SNAP). METHODS: We collected CSF from 266 cognitively normal volunteers participating in a cross-sectional multicenter study (the SIGNAL study) to investigate markers involved in amyloid precursor protein processing (Aβ42, sAPPβ, β-secretase activity), neuronal damage (total-tau [t-tau], phospho-tau [p-tau]), and neuroinflammation (YKL-40). We analyzed the relationship among biomarkers, clinical variables, and the APOE genotype, and compared biomarker levels across the preclinical stages of the National Institute on Aging-Alzheimer's Association classification: stage 0, 1, 2, 3, and SNAP. RESULTS: The median age in the whole cohort was 58.8 years (range 39.8-81.6). Participants in stages 2-3 and SNAP had higher levels of YKL-40 than those in stages 0 and 1. Participants with SNAP had higher levels of sAPPβ than participants in stage 0 and 1. No differences were found between stages 0, 1, and 2-3 in sAPPβ and β-secretase activity in CSF. Age correlated with t-tau, p-tau, and YKL-40. It also correlated with Aβ42, but only in APOE ε4 carriers. Aβ42 correlated positively with t-tau, sAPPβ, and YKL-40 in participants with normal Aβ42. CONCLUSIONS: Our findings suggest that inflammation in the CNS increases in normal aging and is intimately related to markers of neurodegeneration in the preclinical stages of AD and SNAP. sAPPβ and β-secretase activity are not useful diagnostic or staging markers in preclinical AD.
OBJECTIVE: To investigate CSF markers involved in amyloid precursor protein processing, neuronal damage, and neuroinflammation in the preclinical stages of Alzheimer disease (AD) and participants with suspected non-Alzheimer pathology (SNAP). METHODS: We collected CSF from 266 cognitively normal volunteers participating in a cross-sectional multicenter study (the SIGNAL study) to investigate markers involved in amyloid precursor protein processing (Aβ42, sAPPβ, β-secretase activity), neuronal damage (total-tau [t-tau], phospho-tau [p-tau]), and neuroinflammation (YKL-40). We analyzed the relationship among biomarkers, clinical variables, and the APOE genotype, and compared biomarker levels across the preclinical stages of the National Institute on Aging-Alzheimer's Association classification: stage 0, 1, 2, 3, and SNAP. RESULTS: The median age in the whole cohort was 58.8 years (range 39.8-81.6). Participants in stages 2-3 and SNAP had higher levels of YKL-40 than those in stages 0 and 1. Participants with SNAP had higher levels of sAPPβ than participants in stage 0 and 1. No differences were found between stages 0, 1, and 2-3 in sAPPβ and β-secretase activity in CSF. Age correlated with t-tau, p-tau, and YKL-40. It also correlated with Aβ42, but only in APOE ε4 carriers. Aβ42 correlated positively with t-tau, sAPPβ, and YKL-40 in participants with normal Aβ42. CONCLUSIONS: Our findings suggest that inflammation in the CNS increases in normal aging and is intimately related to markers of neurodegeneration in the preclinical stages of AD and SNAP. sAPPβ and β-secretase activity are not useful diagnostic or staging markers in preclinical AD.
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Authors: Ricardo S Osorio; Emma L Ducca; Margaret E Wohlleber; Emily B Tanzi; Tyler Gumb; Akosua Twumasi; Samuel Tweardy; Clifton Lewis; Esther Fischer; Viachaslau Koushyk; Maria Cuartero-Toledo; Mohammed O Sheikh; Elizabeth Pirraglia; Henrik Zetterberg; Kaj Blennow; Shou-En Lu; Lisa Mosconi; Lidia Glodzik; Sonja Schuetz; Andrew W Varga; Indu Ayappa; David M Rapoport; Mony J de Leon Journal: Sleep Date: 2016-06-01 Impact factor: 5.849
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