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. 2021 May;92(5):485-493.
doi: 10.1136/jnnp-2020-324647. Epub 2020 Nov 25.

Plasma microRNA signature in presymptomatic and symptomatic subjects with C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis

Virgilio Kmetzsch  1   2 , Vincent Anquetil  2 , Dario Saracino  1   2   3   4 , Daisy Rinaldi  2   3   4 , Agnès Camuzat  2   5 , Thomas Gareau  2 , Ludmila Jornea  2 , Sylvie Forlani  2 , Philippe Couratier  6 , David Wallon  7 , Florence Pasquier  8 , Noémie Robil  9 , Pierre de la Grange  9 , Ivan Moszer  2 , Isabelle Le Ber  2   3   4   10 , Olivier Colliot  1   2 , Emmanuelle Becker  11 ; PREV-DEMALS study group
Collaborators, Affiliations

Plasma microRNA signature in presymptomatic and symptomatic subjects with C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis

Virgilio Kmetzsch et al. J Neurol Neurosurg Psychiatry. 2021 May.

Abstract

Objective: To identify potential biomarkers of preclinical and clinical progression in chromosome 9 open reading frame 72 gene (C9orf72)-associated disease by assessing the expression levels of plasma microRNAs (miRNAs) in C9orf72 patients and presymptomatic carriers.

Methods: The PREV-DEMALS study is a prospective study including 22 C9orf72 patients, 45 presymptomatic C9orf72 mutation carriers and 43 controls. We assessed the expression levels of 2576 miRNAs, among which 589 were above noise level, in plasma samples of all participants using RNA sequencing. The expression levels of the differentially expressed miRNAs between patients, presymptomatic carriers and controls were further used to build logistic regression classifiers.

Results: Four miRNAs were differentially expressed between patients and controls: miR-34a-5p and miR-345-5p were overexpressed, while miR-200c-3p and miR-10a-3p were underexpressed in patients. MiR-34a-5p was also overexpressed in presymptomatic carriers compared with healthy controls, suggesting that miR-34a-5p expression is deregulated in cases with C9orf72 mutation. Moreover, miR-345-5p was also overexpressed in patients compared with presymptomatic carriers, which supports the correlation of miR-345-5p expression with the progression of C9orf72-associated disease. Together, miR-200c-3p and miR-10a-3p underexpression might be associated with full-blown disease. Four presymptomatic subjects in transitional/prodromal stage, close to the disease conversion, exhibited a stronger similarity with the expression levels of patients.

Conclusions: We identified a signature of four miRNAs differentially expressed in plasma between clinical conditions that have potential to represent progression biomarkers for C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. This study suggests that dysregulation of miRNAs is dynamically altered throughout neurodegenerative diseases progression, and can be detectable even long before clinical onset.

Trial registration number: NCT02590276.

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Conflict of interest statement

Competing interests: OC reports having received consulting fees from AskBio (2020), having received fees for writing a lay audience short paper from Expression Santé (2019), having received speaker fees for a lay audience presentation from Palais de la découverte (2017) and that his laboratory has received grants from Qynapse (2017-present). Members from his laboratory have co-supervised a PhD thesis with myBrainTechnologies (2016-present). OC’s spouse is an employee of myBrainTechnologies (2015-present). OC has submitted a patent to the International Bureau of the World Intellectual Property Organization (PCT/IB2016/0526993, Schiratti J-B, Allassonniere S, Colliot O, Durrleman S, A method for determining the temporal progression of a biological phenomenon and associated methods and devices) (2016). ILB served as a member of advisory boards for Prevail Therapeutic and received research grants from ANR, DGOS, PHRC, Vaincre Alzheimer Association, ARSla Association, Fondation Plan Alzheimer outside of the present work. PG is co-founder and director of GenoSplice. NR is employee at GenoSplice.

Figures

Figure 1
Figure 1
Boxplots depicting the normalised log2 expression levels of the four microRNAs identified as differentially expressed. Box boundaries represent the first and third quartiles and the median is indicated by the line dividing the IQR. The upper whiskers extend to the values that are within 1.5×IQR over the third quartiles. The lower whiskers extend to the values that are within 1.5×IQR under the first quartiles.
Figure 2
Figure 2
ROC (receiver operating characteristic) curves for each pairwise classification (control vs presymptomatic, control vs patient and presymptomatic vs patient) obtained with logistic regression using as features the expression levels of the microRNAs signature (miR-34a-5p, miR-345-5p, miR-200c-3p and miR-10a-3p). Bootstrapped 90% CIs are reported in brackets. AUC, area under the ROC curve.
Figure 3
Figure 3
Number of times each miRNA was found differentially expressed, when performing a repeated 5-fold nested cross-validation for 100 times with different fold splits. In each step of the outer cross-validation loop, four of the five folds were used to identify differentially expressed miRNAs. Since one outer loop consists of five steps, and we performed 100 repetitions, 500 sets of miRNAs were computed for each pairwise comparison between groups, respectively: control vs presymptomatic, control vs patient and presymptomatic vs patient. MiRNAs from the signature computed with the entire data set are highlighted. miRNA, microRNA.
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