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Downregulation of exosomal miR-204-5p and miR-632 as a biomarker for FTD: a GENFI study

Schneider, Raphael, McKeever, Paul, Kim, TaeHyung, Graff, Caroline, van Swieten, John Cornelis, Karydas, Anna, Boxer, Adam, Rosen, Howie, Miller, Bruce L, Laforce Jr, Robert, Galimberti, Daniela, Masellis, Mario, Borroni, Barbara, Zhang, Zhaolei, Zinman, Lorne, Rohrer, Jonathan Daniel, Tartaglia, Maria Carmela, Robertson, Janice·2018·Journal of Neurology, Neurosurgery & Psychiatry
DOI 10.1136/jnnp-2017-317492PMC PMC6045452
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Abstract

Objective: To determine whether exosomal microRNAs (miRNAs) in cerebrospinal fluid (CSF) of patients with frontotemporal dementia (FTD) can serve as diagnostic biomarkers, we assessed miRNA expression in the Genetic Frontotemporal Dementia Initiative (GENFI) cohort and in sporadic FTD. Methods: GENFI participants were either carriers of a pathogenic mutation in progranulin, chromosome 9 open reading frame 72 or microtubule-associated protein tau or were at risk of carrying a mutation because a first-degree relative was a known symptomatic mutation carrier. Exosomes were isolated from CSF of 23 presymptomatic and 15 symptomatic mutation carriers and 11 healthy non-mutation carriers. Expression of 752 miRNAs was measured using quantitative PCR (qPCR) arrays and validated by qPCR using individual primers. MiRNAs found differentially expressed in symptomatic compared with presymptomatic mutation carriers were further evaluated in a cohort of 17 patients with sporadic FTD, 13 patients with sporadic Alzheimer’s disease (AD) and 10 healthy controls (HCs) of similar age. Results: In the GENFI cohort, miR-204-5p and miR-632 were significantly decreased in symptomatic compared with presymptomatic mutation carriers. Decrease of miR-204-5p and miR-632 revealed receiver operator characteristics with an area of 0.89 (90% CI 0.79 to 0.98) and 0.81 (90% CI 0.68 to 0.93), respectively, and when combined an area of 0.93 (90% CI 0.87 to 0.99). In sporadic FTD, only miR-632 was significantly decreased compared with AD and HCs. Decrease of miR-632 revealed an area of 0.90 (90% CI 0.81 to 0.98). Conclusions: Exosomal miR-204-5p and miR-632 have potential as diagnostic biomarkers for genetic FTD and miR-632 also for sporadic FTD.

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Figure 1 Relative expression of miR-204-5p and miR-632 is lower in symptomatic compared with presymptomatic mutation carriers. MiRNA expression was calculated relative to that of healthy non-mutation carriers. Data from individuals with any of the three mutations were grouped, and expression of both miR-204-5p and miR-632 was found to be significantly lower in symptomatic compared with presymptomatic individuals (A). Only data from individuals with a GRN mutation were grouped, and expression of both miR-204-5p and miR-632 was found to be significantly lower in symptomatic compared with presymptomatic individuals (B). Only data from individuals with a C9orf72 mutation were grouped, and expression of miR-204-5p was found to be significantly lower in symptomatic compared with presymptomatic individuals (C). Only data from individuals with any of the three mutations and the bvFTD phenotype were grouped, and expression of both miR-204-5p and miR-632 was found to be significantly lower in symptomatic compared with presymptomatic individuals (D). Welch’s t-tests were corrected for multiple comparisons using the Holm-Sidak method, *P<0.05, ***P<0.005. Mean and SD of mean are shown. C9orf72, chromosome 9 open reading frame 72; GRN, progranulin; bvFTD, behavioural variant FTD.
Figure 1 Relative expression of miR-204-5p and miR-632 is lower in symptomatic compared with presymptomatic mutation carriers. MiRNA expression was calculated relative to that of healthy non-mutation carriers. Data from individuals with any of the three mutations were grouped, and expression of both miR-204-5p and miR-632 was found to be significantly lower in symptomatic compared with presymptomatic individuals (A). Only data from individuals with a GRN mutation were grouped, and expression of both miR-204-5p and miR-632 was found to be significantly lower in symptomatic compared with presymptomatic individuals (B). Only data from individuals with a C9orf72 mutation were grouped, and expression of miR-204-5p was found to be significantly lower in symptomatic compared with presymptomatic individuals (C). Only data from individuals with any of the three mutations and the bvFTD phenotype were grouped, and expression of both miR-204-5p and miR-632 was found to be significantly lower in symptomatic compared with presymptomatic individuals (D). Welch’s t-tests were corrected for multiple comparisons using the Holm-Sidak method, *P<0.05, ***P<0.005. Mean and SD of mean are shown. C9orf72, chromosome 9 open reading frame 72; GRN, progranulin; bvFTD, behavioural variant FTD.CC BY · PubMed Central
Figure 2 ROC curve analysis discriminates symptomatic from presymptomatic mutation carriers. MiR-204-5p and miR-632 expression can discriminate between presymptomatic and symptomatic individuals based on ROC. 90% CI are reported in brackets. Dashed grey lines represent miR-204-5p, dotted black lines represent miR-632 and solid black lines represent the combination of miR-204-5p and miR-632 determined by logistic regression. All mutation carriers (A), GRN mutation carriers (B) and bvFTD phenotype (C) were analysed separately, *P<0.05, **P<0.01, ***P<0.005. #P trend CI includes 1.0. AUC, area under the curve; GRN, progranulin; bvFTD, behavioural variant FTD.
Figure 2 ROC curve analysis discriminates symptomatic from presymptomatic mutation carriers. MiR-204-5p and miR-632 expression can discriminate between presymptomatic and symptomatic individuals based on ROC. 90% CI are reported in brackets. Dashed grey lines represent miR-204-5p, dotted black lines represent miR-632 and solid black lines represent the combination of miR-204-5p and miR-632 determined by logistic regression. All mutation carriers (A), GRN mutation carriers (B) and bvFTD phenotype (C) were analysed separately, *P<0.05, **P<0.01, ***P<0.005. #P trend CI includes 1.0. AUC, area under the curve; GRN, progranulin; bvFTD, behavioural variant FTD.CC BY · PubMed Central
Figure 3 Relative expression of miR-632 is lower in sporadic FTD compared with sporadic AD and HCs. MiRNA expression was calculated relative to that of HCs using the 2−ΔΔCt method. Expression values of HCs, sporadic AD and sporadic FTD were compared. Expression of miR-204-5p was similar between groups (A, left), and expression of miR-632 was significantly lower in FTD using Welch’s t-tests (A, right). MiR-632 expression can discriminate between FTD and non-FTD (HC and AD) based on ROC. 90% CI reported in brackets. Dashed grey line represents HC versus FTD, dotted black line represents AD versus FTD and solid black line represents the combination of HC and AD determined by logistic regression (B). **P<0.01, ***P<0.005, #P trend CI includes 1.0. Mean and SD of mean are shown. AUC, area under the curve; AD, Alzheimer’s disease; FTD, frontotemporal dementia; HC, healthy control.
Figure 3 Relative expression of miR-632 is lower in sporadic FTD compared with sporadic AD and HCs. MiRNA expression was calculated relative to that of HCs using the 2−ΔΔCt method. Expression values of HCs, sporadic AD and sporadic FTD were compared. Expression of miR-204-5p was similar between groups (A, left), and expression of miR-632 was significantly lower in FTD using Welch’s t-tests (A, right). MiR-632 expression can discriminate between FTD and non-FTD (HC and AD) based on ROC. 90% CI reported in brackets. Dashed grey line represents HC versus FTD, dotted black line represents AD versus FTD and solid black line represents the combination of HC and AD determined by logistic regression (B). **P<0.01, ***P<0.005, #P trend CI includes 1.0. Mean and SD of mean are shown. AUC, area under the curve; AD, Alzheimer’s disease; FTD, frontotemporal dementia; HC, healthy control.CC BY · PubMed Central
Figure 4 Venn diagrams of miRNA targets. Overlap of mRNA targeted by miRNAs found decreased in symptomatic compared with presymptomatic mutation carriers (miR-204-5p and miR-632), mRNAs enriched in the human frontal and temporal lobes (frontotemporal) and mRNAs implicated in Wnt signalling (A). Overlap of mRNA targeted by miRNAs less frequently detectable in FTD (miR-23b-3p, miR-326, miR-877-5p, miR-892a, miR-30b-5p and miR-373-3p), more frequently detected in FTD (miR-708-3p), mRNAs enriched in the human frontal and temporal lobes and mRNAs implicated in Wnt signalling, apoptosis, MAPK signalling, endocytosis, notch signalling or neurotrophin signalling (B). Number of validated targets within a pathway are shown in grey cells, and % of targets found in each pathway are shown in brackets below.
Figure 4 Venn diagrams of miRNA targets. Overlap of mRNA targeted by miRNAs found decreased in symptomatic compared with presymptomatic mutation carriers (miR-204-5p and miR-632), mRNAs enriched in the human frontal and temporal lobes (frontotemporal) and mRNAs implicated in Wnt signalling (A). Overlap of mRNA targeted by miRNAs less frequently detectable in FTD (miR-23b-3p, miR-326, miR-877-5p, miR-892a, miR-30b-5p and miR-373-3p), more frequently detected in FTD (miR-708-3p), mRNAs enriched in the human frontal and temporal lobes and mRNAs implicated in Wnt signalling, apoptosis, MAPK signalling, endocytosis, notch signalling or neurotrophin signalling (B). Number of validated targets within a pathway are shown in grey cells, and % of targets found in each pathway are shown in brackets below.CC BY · PubMed Central

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Citations

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Metadata

Authors
Schneider, R., McKeever, P., Kim, T., Graff, C., van Swieten, J. C., Karydas, A., Boxer, A., Rosen, H., Miller, B. L., Laforce Jr, R., Galimberti, D., Masellis, M., Borroni, B., Zhang, Z., Zinman, L., Rohrer, J. D., Tartaglia, M. C., & Robertson, J.
ORCID
Schneider, Raphael
Venue
Journal of Neurology, Neurosurgery & Psychiatry
Publisher
BMJ
Published
2018-02-06
Volume
89
Issue
8
Pages
851-858
ISSN
  • 0022-3050
  • 1468-330X
DOI
10.1136/jnnp-2017-317492
PMC
PMC6045452
Cited by
62
References
4
Language
en

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