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

Abstract

ObjectiveTo 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.MethodsThe 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.ResultsFour 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.ConclusionsWe 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 numberNCT02590276.

microRNA-based predictor for diagnosis of frontotemporal dementia

“…Combination of miR-34a-5p, miR-345-5p, miR-200c-3p and miR-10a-3p, selected previously (56), was consistently inferior to our classifiers in distinguishing between FTD and controls, ALS and controls, and FTD and ALS, with lower AUC values ( Figure 8). Similarly, the classifiers selected in Sheinerman et al, 2017 (42) were inferior to our panels of miRNA classifiers.…”

“…Finally, we tested whether miRNA plasma miRNA classifiers reported in previous works (42,56) perform equally to, better or worse than our classifiers in the training and held out datasets.…”

“…miRNAs play important roles in ALS pathogenesis and in motor neuron survival (35)(36)(37)(38). Accordingly, plasma miRNAs were suggested as diagnostic biomarkers for ALS (39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51) or FTD (42,(52)(53)(54)(55)(56)(57) However, definitive markers have not been reported so far and initial biomarker studies were confounded by cohort size, sample heterogeneity biased or pre -selection of candidate miRNA. Furthermore, diagnosis of comorbid ALS-FTD patients with miRNAs has not been pursued.…”

Plasma NfL levels and longitudinal change rates in C9orf72 and GRN-associated diseases: from tailored references to clinical applications

“…They were recruited through a French research network on FTD/ALS (Inserm RBM 02-59), and Predict to Prevent Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis (PREV-DEMALS) and Natural History Characterization in Symptomatic and Asymptomatic Progranulin Gene Mutation Carriers (Predict-PGRN) national prospective studies. [22][23][24][25] Individuals who had concurrent neurological conditions, other than FTD or ALS, were excluded.…”

RNA Deregulation in Amyotrophic Lateral Sclerosis: The Noncoding Perspective

“…Later, multiple observations deepened the relationship between ALS and deregulated miRNA levels, identifying miRNA subsets that could distinguish patients from healthy subjects. To this purpose, different kinds of biological sources were employed, from blood components [258][259][260][261][262][263][264][265] up to formalin-fixed paraffin-embedded samples [266]. Due to their enriched miRNA content, their fundamental role in intercellular communication, and cargo diffusion in the surrounding environment [267], particular attention was devoted to extracellular vesicles (microvesicles and exosomes).…”