Identification and Preliminary Validation of a Plasma Profile Associated with Cognitive Decline in Dementia and At-Risk Individuals: A Retrospective Cohort Analysis

Article type: Research Article

Authors: Iulita, M. Florencia^{a; 1} | Ganesh, Aravind^{b; c; 1} | Pentz, Rowan^d | Flores Aguilar, Lisi^e | Gubert, Palma^a | Ducatenzeiler, Adriana^a | Christie, Sharon^b | Wilcock, Gordon K.^b | Cuello, A. Claudio^{a; d; e; f; *}

Affiliations: [a] Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada | [b] Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK | [c] Department of Clinical Neurosciences, University of Calgary, Calgary, Canada | [d] Department of Neurology and Neurosurgery, McGill University, Montreal, Canada | [e] Department of Anatomy and Cell Biology, McGill University, Montreal, Canada | [f] Department of Pharmacology, University of Oxford, Oxford, United Kingdom (Visiting Professorship)

Correspondence: [*] Correspondence to: A. Claudio Cuello, OC, MD, DSc, FRSC, Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, 3655 Sir-William-Osler Promenade, Room 1210, Montreal, QC, Canada, H3G 1Y6. Tel.: +1 514 398 3618; Fax: +1 514 398 8317; E:mail claudio.cuello@mcgill.ca.

Note: [1] These authors contributed equally to this work.

Abstract: Biomarker discovery is a major need for earlier dementia diagnosis. We evaluated a plasma signature of amyloid, metallo-proteinases (MMPs), and inflammatory markers in a cohort of at-risk individuals and individuals clinically diagnosed with probable Alzheimer’s disease (pAD). Using multiplex arrays, we measured Aβ40, Aβ42, MMP-1, MMP-3, MMP-9, IFN-γ, TNF-α, IL-6, IL-8, and IL-10 in plasma from 107 individuals followed every 6 months for 3 years. Final diagnoses included: pAD (n = 28), mild cognitive impairment (MCI, n = 30), subjective memory impairment (SMI, n = 30), and asymptomatic (NCI, n = 19). Blood was drawn at final follow-up. We used linear and logistic regressions to examine biomarker associations with prior known decline on the Montreal Cognitive Assessment (MoCA) and the Cambridge Cognitive Examination (CAMCOG); as well disease progression by the time of blood-draw. We derived a biomarker composite from the individual markers, and tested its association with a clinical diagnosis of pAD. Lower Aβ40 and Aβ42 and higher IL-8, IL-10, and TNF-α were associated with greater cognitive decline per the MoCA and CAMCOG. MMP-3 was higher in SMI, MCI, and pAD than NCI. Whereas the other investigative molecules did not differ between groups, composite scores—created using MoCA/CAMCOG-based trends in Aβ40, Aβ42, MMP-1, MMP-3, IL-8, IL-10, and TNF-α— were associated with a final diagnosis of pAD (c-statistic 0.732 versus 0.602 for age-sex alone). Thus, plasma amyloid, MMP, and inflammatory biomarkers demonstrated differences in individuals with cognitive deterioration and/or progression to MCI/pAD. Our findings support studying these markers earlier in the continuum of probable AD as well as in specific dementias.

Keywords: Alzheimer’s disease, dementia, amyloid-β, biomarker, blood, cognitive decline, inflammation, metallo-proteinases, MMP-3, MMP-9, plasma

DOI: 10.3233/JAD-180970

Journal: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 327-341, 2019