Abstract
Introduction: Several neurodegenerative brain proteinopathies, including Alzheimer's disease (AD), are associated with cerebral deposition of insoluble aggregates of α-synuclein. Previous studies reported a trend toward increased cerebrospinal fluid (CSF) α-synuclein (α-syn) concentrations in AD compared with other neurodegenerative diseases and healthy controls. Methods: The pathophysiological role of CSF α-syn in asymptomatic subjects at risk of AD has not been explored. We performed a large-scale cross-sectional observational monocentric study of preclinical individuals at risk for AD (INSIGHT-preAD). Results: We found a positive association between CSF α-syn concentrations and brain β-amyloid deposition measures as mean cortical standard uptake value ratios. We demonstrate positive correlations between CSF α-syn and both CSF t-tau and p-tau181 concentrations. Discussion: Animal models presented evidence, indicating that α-syn may synergistically and directly induce fibrillization of both tau and β-amyloid. Our data indicate an association of CSF α-syn with AD-related pathophysiological mechanisms, during the preclinical phase of the disease.
Original language | English |
---|---|
Pages (from-to) | 1623-1631 |
Number of pages | 9 |
Journal | Alzheimer's and Dementia |
Volume | 14 |
Issue number | 12 |
DOIs | |
State | Published - Dec 2018 |
Keywords
- Alzheimer's disease
- Amyloid PET
- Cerebrospinal fluid
- Monocentric
- Preclinical
- SUVR
- Subjective memory complainers
- Synergistic
- Tau protein
- α-Synuclein
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In: Alzheimer's and Dementia, Vol. 14, No. 12, 12.2018, p. 1623-1631.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Association of cerebrospinal fluid α-synuclein with total and phospho-tau181 protein concentrations and brain amyloid load in cognitively normal subjective memory complainers stratified by Alzheimer's disease biomarkers
AU - Alzheimer Precision Medicine Initiative (APMI)
AU - INSIGHT-preAD Study Group
AU - Vergallo, Andrea
AU - Bun, René Sosata
AU - Toschi, Nicola
AU - Baldacci, Filippo
AU - Zetterberg, Henrik
AU - Blennow, Kaj
AU - Cavedo, Enrica
AU - Lamari, Foudil
AU - Habert, Marie Odile
AU - Dubois, Bruno
AU - Floris, Roberto
AU - Garaci, Francesco
AU - Lista, Simone
AU - Hampel, Harald
AU - Audrain, C.
AU - Auffret, A.
AU - Bakardjian, H.
AU - Batrancourt, B.
AU - Benakki, I.
AU - Benali, H.
AU - Bertin, H.
AU - Bertrand, A.
AU - Boukadida, L.
AU - Cacciamani, F.
AU - Causse, V.
AU - Cherif Touil, S.
AU - Chiesa, P. A.
AU - Colliot, O.
AU - Dalla Barba, G.
AU - Depaulis, M.
AU - Dos Santos, A.
AU - Dubois, M.
AU - Epelbaum, S.
AU - Fontaine, B.
AU - Francisque, H.
AU - Gagliardi, G.
AU - Genin, A.
AU - Genthon, R.
AU - Glasman, P.
AU - Gombert, F.
AU - Hewa, H.
AU - Houot, M.
AU - Jungalee, N.
AU - Kas, A.
AU - Kilani, M.
AU - La Corte, V.
AU - Le Roy, F.
AU - Lehericy, S.
AU - Letondor, C.
AU - O'Bryant, S. E.
N1 - Funding Information: A.V. is supported by Rotary Club Livorno “Mascagni”/the Rotary Foundation (Global Grant No GG1758249). H.Z. is a Wallenberg Academy Fellow and holds grants from the Swedish and European Research Councils as well as the Medical Research Council (UK). K.B. holds the Torsten Söderberg Professorship of Medicine. H.H. is supported by the AXA Research Fund, the “Fondation partenariale Sorbonne Université” and the “Fondation pour la Recherche sur Alzheimer”, Paris, France. Ce travail a bénéficié d'une aide de l'Etat “Investissements d'avenir” ANR-10-IAIHU-06. The research leading to these results has received funding from the program “Investissements d'avenir” ANR-10-IAIHU-06 (Agence Nationale de la Recherche-10-IA Agence Institut Hospitalo-Universitaire-6). Funding Information: This research benefited from the support of the Program “PHOENIX” led by the Sorbonne University Foundation and sponsored by la Fondation pour la Recherche sur Alzheimer. Funding Information: The study was promoted by INSERM in collaboration with ICM, IHU-A-ICM, and Pfizer and has received a support within the “Investissement d'Avenir” (ANR-10-AIHU-06). The study was promoted in collaboration with the “CHU de Bordeaux” (coordination CIC EC7), the promoter of Memento cohort, funded by the Foundation Plan-Alzheimer. The study was further supported by AVID/Lilly. A.V. is supported by Rotary Club Livorno “Mascagni”/the Rotary Foundation (Global Grant No GG1758249). H.Z. is a Wallenberg Academy Fellow and holds grants from the Swedish and European Research Councils as well as the Medical Research Council (UK). K.B. holds the Torsten Söderberg Professorship of Medicine. H.H. is supported by the AXA Research Fund, the “Fondation partenariale Sorbonne Université” and the “Fondation pour la Recherche sur Alzheimer” Paris, France. Ce travail a bénéficié d'une aide de l'Etat “Investissements d'avenir” ANR-10-IAIHU-06. The research leading to these results has received funding from the program “Investissements d'avenir” ANR-10-IAIHU-06 (Agence Nationale de la Recherche-10-IA Agence Institut Hospitalo-Universitaire-6). This research benefited from the support of the Program “PHOENIX” led by the Sorbonne University Foundation and sponsored by la Fondation pour la Recherche sur Alzheimer. Contributors to the Alzheimer Precision Medicine Initiative Working Group (APMI–WG): Aguilar LF (Montréal), Babiloni C (Rome), Baldacci F (Pisa), Benda N (Bonn), Black KL (Los Angeles), Bokde ALW (Dublin), Bonuccelli U (Pisa), Broich K (Bonn), Bun RS (Paris), Cacciola F (Siena), Castrillo J † (Derio), Cavedo E (Paris), Ceravolo R (Pisa), Chiesa PA (Paris), Colliot O (Paris), Coman CM (Paris), Corvol JC (Paris), Cuello AC (Montréal), Cummings JL (Las Vegas), Depypere H (Gent), Dubois B (Paris), Duggento A (Rome), Durrleman S (Paris), Escott-Price V (Cardiff), Federoff H (Irvine), Ferretti MT (Zürich), Fiandaca M (Irvine), Frank RA (Malvern), Garaci F (Rome), Genthon R (Paris), George N (Paris), Giorgi FS (Pisa), Graziani M (Roma), Haberkamp M (Bonn), Habert MO (Paris), Hampel H (Paris), Herholz K (Manchester), Karran E (Cambridge), Kim SH (Seoul), Koronyo Y (Los Angeles), Koronyo-Hamaoui M (Los Angeles), Lamari F (Paris), Langevin T (Minneapolis-Saint Paul), Lehéricy S (Paris), Lista S (Paris), Lorenceau J (Paris), Mapstone M (Irvine), Neri C (Paris), Nisticò R (Rome), Nyasse-Messene F (Paris), O'Bryant SE (Fort Worth), Perry G (San Antonio), Ritchie C (Edinburgh), Rojkova K (Paris), Rossi S (Siena), Santarnecchi E (Siena), Schneider LS (Los Angeles), Sporns O (Bloomington), Toschi N (Rome), Verdooner SR (Sacramento), Vergallo A (Paris), Villain N (Paris), Welikovitch L (Montréal), Woodcock J (Silver Spring), Younesi E (Esch-sur-Alzette). INSIGHT-preAD Study Group: Audrain C, Auffret A, Bakardjian H, Baldacci F, Batrancourt B, Benakki I, Benali H, Bertin H, Bertrand A, Boukadida L, Cacciamani F, Causse V, Cavedo E, Cherif Touil S, Chiesa PA, Colliot O, Dalla Barba G, Depaulis M, Dos Santos A, Dubois B, Dubois M, Epelbaum S, Fontaine B, Francisque H, Gagliardi G, Genin A, Genthon R, Glasman P, Gombert F, Habert MO, Hampel H, Hewa H, Houot M, Jungalee N, Kas A, Kilani M, La Corte V, Le Roy F, Lehericy S, Letondor C, Levy M, Lista S, Lowrey M, Ly J, Makiese O, Masetti I, Mendes A, Metzinger C, Michon A, Mochel F, Nait Arab R, Nyasse F, Perrin C, Poirier F, Poisson C, Potier MC, Ratovohery S, Revillon M, Rojkova K, Santos-Andrade K, Schindler R, Servera MC, Seux L, Simon V, Skovronsky D, Thiebaut M, Uspenskaya O, Vlaincu M. INSIGHT-preAD Scientific Committee Members: Dubois B, Hampel H, Bakardjian H, Colliot O, Habert MO, Lamari F, Mochel F, Potier MC, Thiebaut de Schotten M. Funding Information: The study was promoted by INSERM in collaboration with ICM, IHU-A-ICM, and Pfizer and has received a support within the “Investissement d'Avenir” (ANR-10-AIHU-06). The study was promoted in collaboration with the “CHU de Bordeaux” (coordination CIC EC7), the promoter of Memento cohort, funded by the Foundation Plan-Alzheimer. The study was further supported by AVID/Lilly. Funding Information: Conflict of interests: H.Z. and K.B. are cofounders of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. H.Z. has served at advisory boards of Eli Lilly and Roche Diagnostics and has received travel support from Teva. K.B. has served as a consultant or at advisory boards for Alzheon, BioArctic, Biogen, Eli Lilly, Fujirebio Europe, IBL International, Merck, Novartis, Pfizer, and Roche Diagnostics. M.O.H. has received consultant's honoraria from GE Healthcare, AVID-LILLY, and PIRAMAL. B.D. reports personal fees from Eli Lilly and company. S.L. received lecture honoraria from Roche. H.H. serves as Senior Associate Editor for the Journal Alzheimer's & Dementia; he received lecture fees from Biogen and Roche, research grants from Pfizer, Avid, and MSD Avenir (paid to the institution), travel funding from Functional Neuromodulation, Axovant, Eli Lilly and company, Takeda and Zinfandel, GE-Healthcare, and Oryzon Genomics, consultancy fees from Jung Diagnostics, Cytox Ltd., Axovant, Anavex, Takeda and Zinfandel, GE Healthcare, Oryzon Genomics, and Functional Neuromodulation, and participated in scientific advisory boards of Functional Neuromodulation, Axovant, Anavex, Eli Lilly and company, Cytox Ltd., GE Healthcare, Takeda and Zinfandel, Oryzon Genomics, and Roche Diagnostics. H.H. is co-inventor in the following patents as a scientific expert and has received no royalties: 1) In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Patent Number: 8916388, 2) In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Patent Number: 8298784, 3) Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20120196300, 4) In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100062463, 5) In Vitro Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100035286, 6) In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Publication Number: 20090263822, 7) In Vitro Method for The Diagnosis of Neurodegenerative Diseases Patent Number: 7547553, 8) CSF Diagnostic in Vitro Method for Diagnosis of Dementias and Neuroinflammatory Diseases Publication Number: 20080206797, 9) In Vitro Method for The Diagnosis of Neurodegenerative Diseases Publication Number: 20080199966, and 10) Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20080131921. The other authors report that they have no conflict of interest to disclose. Publisher Copyright: © 2018 the Alzheimer's Association
PY - 2018/12
Y1 - 2018/12
N2 - Introduction: Several neurodegenerative brain proteinopathies, including Alzheimer's disease (AD), are associated with cerebral deposition of insoluble aggregates of α-synuclein. Previous studies reported a trend toward increased cerebrospinal fluid (CSF) α-synuclein (α-syn) concentrations in AD compared with other neurodegenerative diseases and healthy controls. Methods: The pathophysiological role of CSF α-syn in asymptomatic subjects at risk of AD has not been explored. We performed a large-scale cross-sectional observational monocentric study of preclinical individuals at risk for AD (INSIGHT-preAD). Results: We found a positive association between CSF α-syn concentrations and brain β-amyloid deposition measures as mean cortical standard uptake value ratios. We demonstrate positive correlations between CSF α-syn and both CSF t-tau and p-tau181 concentrations. Discussion: Animal models presented evidence, indicating that α-syn may synergistically and directly induce fibrillization of both tau and β-amyloid. Our data indicate an association of CSF α-syn with AD-related pathophysiological mechanisms, during the preclinical phase of the disease.
AB - Introduction: Several neurodegenerative brain proteinopathies, including Alzheimer's disease (AD), are associated with cerebral deposition of insoluble aggregates of α-synuclein. Previous studies reported a trend toward increased cerebrospinal fluid (CSF) α-synuclein (α-syn) concentrations in AD compared with other neurodegenerative diseases and healthy controls. Methods: The pathophysiological role of CSF α-syn in asymptomatic subjects at risk of AD has not been explored. We performed a large-scale cross-sectional observational monocentric study of preclinical individuals at risk for AD (INSIGHT-preAD). Results: We found a positive association between CSF α-syn concentrations and brain β-amyloid deposition measures as mean cortical standard uptake value ratios. We demonstrate positive correlations between CSF α-syn and both CSF t-tau and p-tau181 concentrations. Discussion: Animal models presented evidence, indicating that α-syn may synergistically and directly induce fibrillization of both tau and β-amyloid. Our data indicate an association of CSF α-syn with AD-related pathophysiological mechanisms, during the preclinical phase of the disease.
KW - Alzheimer's disease
KW - Amyloid PET
KW - Cerebrospinal fluid
KW - Monocentric
KW - Preclinical
KW - SUVR
KW - Subjective memory complainers
KW - Synergistic
KW - Tau protein
KW - α-Synuclein
UR - http://www.scopus.com/inward/record.url?scp=85054461082&partnerID=8YFLogxK
U2 - 10.1016/j.jalz.2018.06.3053
DO - 10.1016/j.jalz.2018.06.3053
M3 - Article
C2 - 30055132
AN - SCOPUS:85054461082
SN - 1552-5260
VL - 14
SP - 1623
EP - 1631
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 12
ER -