TY - JOUR
T1 - CSF progranulin increases in the course of Alzheimer's disease and is associated with sTREM2, neurodegeneration and cognitive decline
AU - the Dominantly Inherited Alzheimer Network
AU - the Alzheimer's Disease Neuroimaging Initiative
AU - Suárez-Calvet, Marc
AU - Capell, Anja
AU - Araque Caballero, Miguel Ángel
AU - Morenas-Rodríguez, Estrella
AU - Fellerer, Katrin
AU - Franzmeier, Nicolai
AU - Kleinberger, Gernot
AU - Eren, Erden
AU - Deming, Yuetiva
AU - Piccio, Laura
AU - Karch, Celeste M.
AU - Cruchaga, Carlos
AU - Paumier, Katrina
AU - Bateman, Randall J.
AU - Fagan, Anne M.
AU - Morris, John C.
AU - Levin, Johannes
AU - Danek, Adrian
AU - Jucker, Mathias
AU - Masters, Colin L.
AU - Rossor, Martin N.
AU - Ringman, John M.
AU - Shaw, Leslie M.
AU - Trojanowski, John Q.
AU - Weiner, Michael
AU - Ewers, Michael
AU - Haass, Christian
N1 - Funding Information:
We would like to thank Tammie Benzinger, Krista Moulder, Peter Wang, Chengjie Xiong, Michael Donohue, Thomas Montine, Jihn K. Hsiao, Jacob Alexander and all the researchers in the DIAN and in the ADNI initiatives. We also thank Brigitte Nuscher and Nicole Exner for technical assistance and José Luís Molinuevo and Nicholas Ashton for critically reading the manuscript and helpful discussion. This work was supported by the Deutsche Forschungsgemeinschaft (DFG) within the framework of the Munich Cluster for Systems Neurology (EXC 1010 SyNergy), a DFG funded Koselleck Project (HA1737/16-1 to C.H.) and the FTD Biomarker Award. Data collection and sharing for this project were supported by The Dominantly Inherited Alzheimer's Network (DIAN, UF1AG032438) funded by the National Institute on Aging (NIA), the German Center for Neurodegenerative Diseases (DZNE), Raul Carrea Institute for Neurological Research (FLENI), Partial support by the Research and Development Grants for Dementia from Japan Agency for Medical Research and Development, AMED, and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI). This manuscript has been reviewed by DIAN study investigators for scientific content and consistency of data interpretation with previous DIAN study publications. We acknowledge the altruism of the participants and their families and contributions of the DIAN research and support staff at each of the participating sites for their contributions to this study. This work was also supported by grants from the HHS | NIH | National Institute on Aging (NIA) (R01AG044546, RF1AG053303, R01AG058501 and U01AG058922). YD is supported by an HHS | NIH | National Institute of Mental Health (NIMH) institutional training grant (T32MH014877). LP was supported by a grant from the Fondazione Italiana Sclerosi Multipla (FISM) (FISM 2017/R/20). EM was supported by a grant from the Ad-Hoc Committee for Young Neurologist (Spanish Society of Neurology) and Health Institute Carlos III (funding programme for the mobility of the researchers).
Funding Information:
We would like to thank Tammie Benzinger, Krista Moulder, Peter Wang, Chengjie Xiong, Michael Donohue, Thomas Montine, Jihn K. Hsiao, Jacob Alexander and all the researchers in the DIAN and in the ADNI initiatives. We also thank Brigitte Nuscher and Nicole Exner for technical assistance and José Luís Molinuevo and Nicholas Ashton for critically reading the manuscript and helpful discussion. This work was supported by the Deutsche Forschungsge-meinschaft (DFG) within the framework of the Munich Cluster for Systems Neurology (EXC 1010 SyNergy), a DFG funded Koselleck Project (HA1737/16-1 to C.H.) and the FTD Biomarker Award. Data collection and sharing for this project were supported by The Dominantly Inherited Alzheimer’s Network (DIAN, UF1AG032438) funded by the National Institute on Aging (NIA), the German Center for Neurodegenerative Diseases (DZNE), Raul Carrea Institute for Neurological Research (FLENI), Partial support by the Research and Development Grants for Dementia from Japan Agency for Medical Research and Development, AMED, and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI). This manuscript has been reviewed by DIAN study investigators for scientific content and consistency of data interpretation with previous DIAN study publications. We acknowledge the altruism of the participants and their families and contributions of the DIAN research and support staff at each of the participating sites for their contributions to this study. This work was also supported by grants from the HHS | NIH | National Institute on Aging (NIA) (R01AG044546, RF1AG053303, R01AG058501 and U01AG058922). YD is supported by an HHS | NIH | National Institute of Mental Health (NIMH) institutional training grant (T32MH014877). LP was supported by a grant from the Fondazione Italiana Sclerosi Multipla (FISM) (FISM 2017/R/20). EM was supported by a grant from the Ad-Hoc Committee for Young Neurologist (Spanish Society of Neurology) and Health Institute Carlos III (funding programme for the mobility of the researchers).
Publisher Copyright:
© 2018 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2018/12
Y1 - 2018/12
N2 - Progranulin (PGRN) is predominantly expressed by microglia in the brain, and genetic and experimental evidence suggests a critical role in Alzheimer's disease (AD). We asked whether PGRN expression is changed in a disease severity-specific manner in AD. We measured PGRN in cerebrospinal fluid (CSF) in two of the best-characterized AD patient cohorts, namely the Dominant Inherited Alzheimer's Disease Network (DIAN) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). In carriers of AD causing dominant mutations, cross-sectionally assessed CSF PGRN increased over the course of the disease and significantly differed from non-carriers 10 years before the expected symptom onset. In late-onset AD, higher CSF PGRN was associated with more advanced disease stages and cognitive impairment. Higher CSF PGRN was associated with higher CSF soluble TREM2 (triggering receptor expressed on myeloid cells 2) only when there was underlying pathology, but not in controls. In conclusion, we demonstrate that, although CSF PGRN is not a diagnostic biomarker for AD, it may together with sTREM2 reflect microglial activation during the disease.
AB - Progranulin (PGRN) is predominantly expressed by microglia in the brain, and genetic and experimental evidence suggests a critical role in Alzheimer's disease (AD). We asked whether PGRN expression is changed in a disease severity-specific manner in AD. We measured PGRN in cerebrospinal fluid (CSF) in two of the best-characterized AD patient cohorts, namely the Dominant Inherited Alzheimer's Disease Network (DIAN) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). In carriers of AD causing dominant mutations, cross-sectionally assessed CSF PGRN increased over the course of the disease and significantly differed from non-carriers 10 years before the expected symptom onset. In late-onset AD, higher CSF PGRN was associated with more advanced disease stages and cognitive impairment. Higher CSF PGRN was associated with higher CSF soluble TREM2 (triggering receptor expressed on myeloid cells 2) only when there was underlying pathology, but not in controls. In conclusion, we demonstrate that, although CSF PGRN is not a diagnostic biomarker for AD, it may together with sTREM2 reflect microglial activation during the disease.
KW - Alzheimer's disease
KW - TREM2
KW - biomarker
KW - microglia
KW - progranulin
UR - http://www.scopus.com/inward/record.url?scp=85057307296&partnerID=8YFLogxK
U2 - 10.15252/emmm.201809712
DO - 10.15252/emmm.201809712
M3 - Article
C2 - 30482868
AN - SCOPUS:85057307296
VL - 10
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
SN - 1757-4676
IS - 12
M1 - e9712
ER -