Insulin-like growth factor binding protein-2 in at-risk adults and autopsy-confirmed Alzheimer brains
Author:
Quesnel Marc James12, Labonté Anne23, Picard Cynthia23, Zetterberg Henrik456789ORCID, Blennow Kaj451011, Brinkmalm Ann45, Villeneuve Sylvia123, Poirier Judes123, Tam Angela12131415, Labonté Anne1213, Binette Alexa Pichet121316, Faubert Anne-Marie13, Mathieu Axel13, Madjar Cécile121317, Carrier Charles Edouard13, Dansereau Christian1415, Kazazian Christina121316, Lepage Claude1617, Picard Cynthia121316, Maillet David1316, Michaud Diane13, Couture Doris13, Dea Doris1213, Cuello Claudio16, Barkun Alan16, Evans Alan121617, Courcot Blandine13, Tardif Christine1213, Debacker Clément12131617, Jack Clifford R18, Fontaine David1213, Knopman David S18, Multhaup Gerhard16, Near Jamie1316, Leoutsakos Jeannie-Marie19, Maltais Jean-Robert12131620, Brandt Jason19, Pruessner Jens121316, Morris John C21, Breitner John C S121316, Poirier Judes121316, Cheewakriengkrai Laksanun12131620, Münter Lisa-Marie16, Collins Louis121617, Chakravarty Mallar121316, Sager Mark A22, Dauar-Tedeschi Marina12131620, Eisenberg Mark16, Rajah Natasha121316, Aisen Paul23, Toussaint Paule-Joanne1617, Rosa-Neto Pedro12131620, Bellec Pierre121415, Kostopoulos Penelope1617, Etienne Pierre121316, Tariot Pierre N24, Orban Pierre12131415, Sperling Reisa A25, Hoge Rick121617, Thomas Ronald G26, Gauthier Serge12131620, Craft Suzanne27, Villeneuve Sylvia121316, Montine Thomas J28, Nair Vasavan131620, Bohbot Véronique121316, Venugopalan Vinod1213, Fonov Vladimir1617, Ituria-Medina Yasser121617, Khachaturian Zaven S29, Teigner Eduard1213, Anthal Elena1213, Yu Elsa1316, Ferdinand Fabiola1213, Pogossova Galina1213, Mayrand Ginette1213, Duclair Guerda1213, Gagné Guylaine1213, Newbold-Fox Holly13, Leppert Illana12131617, Vallée Isabelle1213, Vogel Jacob1617, Tremblay-Mercier Jennifer1213, Frenette Joanne1213, Frappier Josée1213, Kat Justin121317, Miron Justin121316, Wan Karen1213, Mahar Laura1213, Carmo Leopoldina1213, Théroux Louise1213, Dadar Mahsa1617, Dufour Marianne1213, Lafaille-Magnan Marie-Elyse121316, Appleby Melissa1213, Savard Mélissa1213, Tuwaig Miranda121316, Petkova Mirela12131617, Rioux Pierre1617, Meyer Pierre-François121316, El-Khoury Rana1213, Gordon Renee121316, Giles Renuka1213, Das Samir1617, Wang Seqian131620, Tabrizi Shirin1213, Mathotaarachchi Sulantha131620, Dubuc Sylvie13, Lee Tanya1213, Beaudry Thomas1320, Gervais Valérie1213, Pagé Véronique13, Gonneaud Julie121316, Ayranci Gülebru121316, Pascoal Tharick A12131620, Desautels René13, Benbouhoud Fatiha13, Saint-Fort Eunice Farah13, Verfaillie Sander C J121330, Farzin Sarah13, Salaciak Alyssa13, Tullo Stephanie1316, Vachon-Presseau Etienne1331, Daoust Leslie-Ann12, Köbe Theresa1216, Spreng Nathan17, McSweeney Melissa16, Nilsson Nathalie121316, Pishnamazi Morteza121316, Bedetti Christophe13, Hudon Louise, Greco Claudia1213, Chapleau Marianne1213, St-Onge Frederic121316, Boutin Sophie1213, Geddes Maiya R1213161720, Ducharme Simon12131617, Jean Gabriel1213, Sylvain Elisabeth1213, Élie Marie-Josée1213, Leblond-Baccichet Gloria1213, Ozlen Hazal1316, Bailly Julie13, Mohammediyan Bery1316, Chen Yalin12, Remz Jordana13, Soucy Jean-Paul1617, Baril Andrée-Ann1216, Badawy Mohamed1617, Dery Christine12, Raoult Jean-Michel1213, Menes Julien16, Prenevost Nathalie1217, Poirier Alexandre16, Tremblay Michel16, Aumont Gabriel16, Quesnel Marc16, Ao Jiarui16,
Affiliation:
1. McGill University, Department of Psychiatry , Montréal, Québec, Canada, H3A 1A1 2. Douglas Mental Health University Institute, Research Centre , Montréal, Québec, Canada, H4H 1R3 3. Centre for the Studies in the Prevention of Alzheimer’s Disease, Douglas Mental Health University Institute , Montréal, Québec, Canada, H4H 1R3 4. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden 5. Clinical Neurochemistry Department, Sahlgrenska University Hospital , Mölndal , Sweden 6. Department of Neurodegenerative Disease, UCL Institute of Neurology , London, WC1N 3BG, UK 7. UK Dementia Research Institute at UCL , London, WC1E 6BT, UK 8. Hong Kong Center for Neurodegenerative Diseases , Hong Kong , China 9. Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison , Madison, WI 53792-2420 USA 10. Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University , 21 414–75646 Paris Cedex 13, Paris , France 11. Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC , Hefei, P.R. China 12. STOP-AD CENTRE, Centre For Studies On Prevention Of Alzheimer's Disease , Montreal, Qc , Canada 13. Douglas Mental Health University Institute Research Centre, Affiliated With McGill University , Montreal, Qc , Canada 14. Centre De Recherche De L'Institut Universitaire De Gériatrie De Montreal , Qc , Canada 15. Université De Montréal , Montreal, Qc , Canada 16. McGill University , Montreal, Qc , Canada 17. Montreal Neurological Institute And Hospital , Montreal, Qc , Canada 18. Mayo Clinic , Rochester, MN , USA 19. John Hopkins University , Baltimore, MD , USA 20. McGill University Research Centre For Studies In Aging , Montreal, Qc , Canada 21. Washington University School Of Medecine In St-Louis , MO , USA 22. Wisconsin Alzheimer's Institute, UW School Of Medicine And Public Health , Milwaukee, WI , USA 23. University Of Southern California's Alzheimer's Therapeutic Research Institute , San Diego, CA , USA 24. Banner Alzheimer Institute , Phoenix, AZ , USA 25. Center For Alzheimer's Research And Treatment Harvard Medical School , Boston, MA , USA 26. University California, San Diego, School Of Medicine , La Jolla, CA , USA 27. Wake Forest School Of Medicine , Winston-Salem, NC , USA 28. Washington University , Seattle, WA , USA 29. Khachaturian & Associates Inc , Potomac, MD , USA 30. Alzheimer Center, VU University Amsterdam , Amsterdam , Netherlands 31. Northwestern University , Chicago, IL , USA
Abstract
Abstract
Insulin, insulin-like growth factors (IGF) and their receptors are highly expressed in the adult hippocampus. Thus, disturbances in the insulin-IGF signaling pathway may account for the selective vulnerability of the hippocampus to nascent Alzheimer’s disease (AD) pathology. In the present study, we examined the predominant IGF-binding protein (IGFBP) in the cerebrospinal fluid (CSF) – IGFBP2.
CSF was collected from 109 asymptomatic members of the parental history-positive PREVENT-AD cohort. CSF levels of IGFBP2, core AD biomarkers and synaptic biomarkers were measured using proximity extension assay, ELISA and mass spectrometry. Cortical amyloid-beta (Aβ) and tau deposition were examined using 18F-NAV4694 and flortaucipir. Cognitive assessments were performed up to 8 years of follow-up, using the Repeatable Battery for the Assessment of Neuropsychological Status. T1-weighted structural MRI scans were acquired, and neuroimaging analyses were performed on pre-specified temporal and parietal brain regions. Next, in an independent cohort, we allocated 241 dementia-free ADNI-1 participants into four stages of AD progression based on the biomarkers CSF Aβ42 and total-tau (t-tau). In this analysis, differences in CSF and plasma IGFBP2 levels were examined across the pathological stages. Finally, IGFBP2 mRNA and protein levels were examined in the frontal cortex of 55 autopsy-confirmed AD and 31 control brains from the QFP cohort, a unique population isolate from Eastern Canada.
CSF IGFBP2 progressively increased over 5 years in asymptomatic PREVENT-AD participants. Baseline CSF IGFBP2 was positively correlated with CSF AD biomarkers and synaptic biomarkers, and was negatively correlated with longitudinal changes in delayed memory (P = 0.024) and visuospatial abilities (P = 0.019). CSF IGFBP2 was negatively correlated at a trend-level with entorhinal cortex volume (P = 0.082) and cortical thickness in the piriform (P = 0.039), inferior temporal (P = 0.008), middle temporal (P = 0.014) and precuneus (P = 0.033) regions. In ADNI-1, CSF (P = 0.009) and plasma (P = 0.001) IGFBP2 were significantly elevated in Stage 2 (CSF Aβ(+)/t-tau(+)). In survival analyses in ADNI-1, elevated plasma IGFBP2 was associated with a greater rate of AD conversion (HR = 1.62, P = 0.021). In the QFP cohort, IGFBP2 mRNA was reduced (P = 0.049), however IGFBP2 protein levels did not differ in the frontal cortex of autopsy-confirmed AD brains (P = 0.462).
Nascent AD pathology may induce an upregulation in IGFBP2, in asymptomatic individuals. CSF and plasma IGFBP2 may be valuable markers for identifying CSF Aβ(+)/t-tau(+) individuals and those with a greater risk of AD conversion.
Publisher
Oxford University Press (OUP)
Subject
Neurology (clinical)
Cited by
3 articles.
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