Ignacio Illán-Gala1, Daniel Alcolea1, Victor Montal1, Oriol Dols-Icardo1, Laia Muñoz1, Noemi de Luna1, Janina Turón-Sans1, Elena Cortés-Vicente1, Ma Belén Sánchez-Saudinós1, Andrea Subirana1, Isabel Sala1, Rafael Blesa1, Jordi Clarimón1, Juan Fortea1, Ricard Rojas-García2, Alberto Lleó2. 1. From the Sant Pau Memory Unit, Department of Neurology, Biomedical Research Institute Sant Pau (I.I.-G., D.A., V.M., O.D.-I., L.M., M.B.S.-S., A.S., I.S., R.B., J.C., J.F., A.L.), and Neuromuscular Diseases Unit, Department of Neurology (N.d.L., J.T.-S., E.C.-V., R.R.-G.), Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (I.I.-G., D.A., V.M., O.D.-I., R.B., J.C., J.F., A.L.); and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (N.d.L., J.T.-S., E.C.-V., R.R.-G.), Madrid, Spain. 2. From the Sant Pau Memory Unit, Department of Neurology, Biomedical Research Institute Sant Pau (I.I.-G., D.A., V.M., O.D.-I., L.M., M.B.S.-S., A.S., I.S., R.B., J.C., J.F., A.L.), and Neuromuscular Diseases Unit, Department of Neurology (N.d.L., J.T.-S., E.C.-V., R.R.-G.), Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (I.I.-G., D.A., V.M., O.D.-I., R.B., J.C., J.F., A.L.); and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (N.d.L., J.T.-S., E.C.-V., R.R.-G.), Madrid, Spain. alleo@santpau.cat rrojas@santpau.cat.
Abstract
OBJECTIVE: To investigate the clinical utility of 3 CSF biomarkers along the clinical spectrum of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). METHODS: We analyzed 3 CSF biomarkers: the soluble β-fragment of amyloid precursor protein (sAPPβ), YKL-40, and neurofilament light (NfL) in FTD (n = 86), ALS (n = 38), and a group of age-matched cognitively normal controls (n = 49). Participants with FTD with a CSF profile of Alzheimer disease were excluded. We compared cross-sectional biomarker levels between groups, studied their correlation with cognitive and functional scales (global cognitive z score, frontotemporal lobar degeneration Clinical Dementia Rating, revised ALS Functional Rating Scale, and ALS progression rate), survival, and cortical thickness. RESULTS: We found increased levels of YKL-40 and decreased levels of sAPPβ in both FTD and ALS groups compared to controls. The lowest sAPPβ levels and sAPPβ/YKL-40 ratio were found in the FTD group. In FTD, sAPPβ and the sAPPβ/YKL-40 ratio correlated with the disease severity. In the whole ALS-FTD spectrum, NfL levels and the NfL:sAPPβ ratio correlated with global cognitive performance (r = -0.41, p < 0.001 and r = -0.44, p < 0.001, respectively). In the ALS group, YKL-40 correlated with disease progression rate (r = 0.51, p = 0.001) and was independently associated with shorter survival. In both FTD and ALS groups, the sAPPβ/YKL-40 ratio showed a positive correlation with cortical thickness in frontotemporal regions. CONCLUSIONS: sAPPβ, YKL-40, and NfL could represent valuable tools for the staging and prognosis of patients within the ALS-FTD clinical spectrum. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that CSF levels of sAPPβ, YKL-40, and NfL are useful to assess frontotemporal neurodegeneration and the progression rate in the ALS-FTD continuum.
OBJECTIVE: To investigate the clinical utility of 3 CSF biomarkers along the clinical spectrum of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). METHODS: We analyzed 3 CSF biomarkers: the soluble β-fragment of amyloid precursor protein (sAPPβ), YKL-40, and neurofilament light (NfL) in FTD (n = 86), ALS (n = 38), and a group of age-matched cognitively normal controls (n = 49). Participants with FTD with a CSF profile of Alzheimer disease were excluded. We compared cross-sectional biomarker levels between groups, studied their correlation with cognitive and functional scales (global cognitive z score, frontotemporal lobar degeneration Clinical Dementia Rating, revised ALS Functional Rating Scale, and ALS progression rate), survival, and cortical thickness. RESULTS: We found increased levels of YKL-40 and decreased levels of sAPPβ in both FTD and ALS groups compared to controls. The lowest sAPPβ levels and sAPPβ/YKL-40 ratio were found in the FTD group. In FTD, sAPPβ and the sAPPβ/YKL-40 ratio correlated with the disease severity. In the whole ALS-FTD spectrum, NfL levels and the NfL:sAPPβ ratio correlated with global cognitive performance (r = -0.41, p < 0.001 and r = -0.44, p < 0.001, respectively). In the ALS group, YKL-40 correlated with disease progression rate (r = 0.51, p = 0.001) and was independently associated with shorter survival. In both FTD and ALS groups, the sAPPβ/YKL-40 ratio showed a positive correlation with cortical thickness in frontotemporal regions. CONCLUSIONS: sAPPβ, YKL-40, and NfL could represent valuable tools for the staging and prognosis of patients within the ALS-FTD clinical spectrum. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that CSF levels of sAPPβ, YKL-40, and NfL are useful to assess frontotemporal neurodegeneration and the progression rate in the ALS-FTD continuum.
Authors: Ione O C Woollacott; Jennifer M Nicholas; Carolin Heller; Martha S Foiani; Katrina M Moore; Lucy L Russell; Ross W Paterson; Ashvini Keshavan; Jonathan M Schott; Jason D Warren; Amanda Heslegrave; Henrik Zetterberg; Jonathan D Rohrer Journal: Dement Geriatr Cogn Disord Date: 2020-04-28 Impact factor: 2.959
Authors: Ignacio Illán-Gala; Victor Montal; Sergi Borrego-Écija; Eduard Vilaplana; Jordi Pegueroles; Daniel Alcolea; Belén Sánchez-Saudinós; Jordi Clarimón; Janina Turón-Sans; Nuria Bargalló; Sofía González-Ortiz; Howard J Rosen; Maria Luisa Gorno-Tempini; Bruce L Miller; Albert Lladó; Ricard Rojas-García; Rafael Blesa; Raquel Sánchez-Valle; Alberto Lleó; Juan Fortea Journal: Brain Date: 2019-04-01 Impact factor: 13.501
Authors: Björn F Vahsen; Elizabeth Gray; Alexander G Thompson; Olaf Ansorge; Daniel C Anthony; Sally A Cowley; Kevin Talbot; Martin R Turner Journal: Nat Rev Neurol Date: 2021-04-29 Impact factor: 42.937
Authors: Brian V Lananna; Celia A McKee; Melvin W King; Jorge L Del-Aguila; Julie M Dimitry; Fabiana H G Farias; Collin J Nadarajah; David D Xiong; Chun Guo; Alexander J Cammack; Jack A Elias; Jinsong Zhang; Carlos Cruchaga; Erik S Musiek Journal: Sci Transl Med Date: 2020-12-16 Impact factor: 17.956
Authors: Ignacio Illán-Gala; Victor Montal; Jordi Pegueroles; Eduard Vilaplana; Daniel Alcolea; Oriol Dols-Icardo; Noemi de Luna; Janina Turón-Sans; Elena Cortés-Vicente; Luis Martinez-Roman; Maria Belén Sánchez-Saudinós; Andrea Subirana; Laura Videla; Isabel Sala; Isabel Barroeta; Sílvia Valldeneu; Rafael Blesa; Jordi Clarimón; Alberto Lleó; Juan Fortea; Ricard Rojas-García Journal: Neurology Date: 2020-09-10 Impact factor: 9.910