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. 2021 Jan 27;11(1):78.
doi: 10.1038/s41398-020-01184-8.

MiRNA-15b and miRNA-125b are associated with regional Aβ-PET and FDG-PET uptake in cognitively normal individuals with subjective memory complaints

Andrea Vergallo #  1 , Simone Lista #  2   3   4 , Yuhai Zhao  5   6 , Pablo Lemercier  2   3   4 , Stefan J Teipel  7   8 , Marie-Claude Potier  9 , Marie-Odile Habert  10   11   12 , Bruno Dubois  2   3   4 , Walter J Lukiw  13   14   15 , Harald Hampel  2 ; INSIGHT-preAD study group; Alzheimer Precision Medicine Initiative (APMI)
Collaborators, Affiliations

MiRNA-15b and miRNA-125b are associated with regional Aβ-PET and FDG-PET uptake in cognitively normal individuals with subjective memory complaints

Andrea Vergallo et al. Transl Psychiatry. .

Abstract

There is substantial experimental evidence for dysregulation of several microRNA (miRNA) expression levels in Alzheimer's disease (AD). MiRNAs modulate critical brain intracellular signaling pathways and are associated with AD core pathophysiological mechanisms. First, we conducted a real-time quantitative PCR-based pilot study to identify a set of brain-enriched miRNAs in a monocentric cohort of cognitively normal individuals with subjective memory complaints, a condition associated with increased risk of AD. Second, we investigated the impact of age, sex, and the Apolipoprotein E ε4 (APOE ε4) allele, on the identified miRNA plasma concentrations. In addition, we explored the cross-sectional and longitudinal association of the miRNAs plasma concentrations with regional brain metabolic uptake using amyloid-β (Aβ)-positron emission tomography (Aβ-PET) and 18F-fluorodeoxyglucose-PET (18F-FDG-PET). We identified a set of six brain-enriched miRNAs-miRNA-125b, miRNA-146a, miRNA-15b, miRNA-148a, miRNA-26b, and miRNA-100. Age, sex, and APOE ε4 allele were not associated with individual miRNA abundance. MiRNA-15b concentrations were significantly lower in the Aβ-PET-positive compared to Aβ-PET-negative individuals. Furthermore, we found a positive effect of the miRNA-15b*time interaction on regional metabolic 18F-FDG-PET uptake in the left hippocampus. Plasma miRNA-125b concentrations, as well as the miRNA-125b*time interaction (over a 2-year follow-up), were negatively associated with regional Aβ-PET standard uptake value ratio in the right anterior cingulate cortex. At baseline, we found a significantly negative association between plasma miRNA-125b concentrations and 18F-FDG-PET uptake in specific brain regions. In an asymptomatic at-risk population for AD, we show significant associations between plasma concentrations of miRNA-125b and miRNA-15b with core neuroimaging biomarkers of AD pathophysiology. Our results, coupled with existing experimental evidence, suggest a potential protective anti-Aβ effect of miRNA-15b and a biological link between miRNA-125b and Aβ-independent neurotoxic pathways.

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Conflict of interest statement

H.H. is an employee of Eisai Inc. and serves as Senior Associate Editor for the Journal Alzheimer’s & Dementia and does not receive any fees or honoraria since May 2019; before May 2019 he had received lecture fees from Servier, Biogen and Roche, research grants from Pfizer, Avid, and MSD Avenir (paid to the institution), travel funding from Eisai, Functional Neuromodulation, Axovant, Eli Lilly and company, Takeda and Zinfandel, GE Healthcare and Oryzon Genomics, consultancy fees from Qynapse, 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, Eisai, Eli Lilly and company, Cytox Ltd., GE Healthcare, Takeda and Zinfandel, Oryzon Genomics and Roche Diagnostics. He is co-inventor in the following patents as a scientific expert and has received no royalties: • In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Patent Number: 8916388 • In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Patent Number: 8298784 • Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20120196300 • In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100062463 • In Vitro Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100035286 • In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Publication Number: 20090263822 • In Vitro Method for The Diagnosis of Neurodegenerative Diseases Patent Number: 7547553 • CSF Diagnostic in Vitro Method for Diagnosis of Dementias and Neuroinflammatory Diseases Publication Number: 20080206797 • In Vitro Method for The Diagnosis of Neurodegenerative Diseases Publication Number: 20080199966 • Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20080131921. A.V. is an employee of Eisai Inc. He does not receive any fees or honoraria since November 2019. Before November 2019 he had he received lecture honoraria from Roche, MagQu LLC, and Servier. S.L. received lecture honoraria from Roche and Servier. Y.Z., P.L., S.J.T., M.C.P., M.O.H., B.D., and W.J.L. declare no conflict of interest.

Figures

Fig. 1
Fig. 1. miRNA15b is significantly lower in the Aβ-PET negative subgroup compared with the Aβ-PET positive.
*Kruskal–Wallis one-way ANOVA on ranks test; p value: 0.045 (see Table 1 for descriptive data). Plasma miR-15b concentration is reported in terms of relative quantity. PET positron emission tomography, Aβ amyloid beta, n.s. not significant, miRNA microRNA.
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