microRNA-based predictor for diagnosis of frontotemporal dementia

Abstract

Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder characterized by frontal and temporal lobe atrophy, typically manifesting with behavioural or language impairment. Because of its heterogeneity and lack of available diagnostic laboratory tests there can be a substantial delay in diagnosis. Cell-free, circulating, microRNAs are increasingly investigated as biomarkers for neurodegeneration, but their value in FTD is not yet established. In this study, we investigate microRNAs as biomarkers for FTD diagnosis. We performed next generation small RNA sequencing on cell-free plasma from 52 FTD cases and 21 controls. The analysis revealed the diagnostic importance of 20 circulating endogenous miRNAs in distinguishing FTD cases from controls. The study was repeated in an independent second cohort of 117 FTD cases and 35 controls. The combinatorial microRNA signature from the first cohort, precisely diagnosed FTD samples in a second cohort. To further increase the generalizability of the prediction, we implemented machine learning techniques in a merged dataset of the two cohorts, which resulted in a comparable or improved classification precision with a smaller panel of miRNA classifiers. In addition, there are intriguing molecular commonalities with cell free miRNA signature in ALS, a motor neuron disease that resides on a pathological continuum with FTD. However, the signature that describes the ALS-FTD spectrum is not shared with blood miRNA profiles of patients with multiple sclerosis. Thus, microRNAs are promising FTD biomarkers that might enable earlier detection of FTD and improve accurate identification of patients for clinical trials

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

“…Previous studies have shown the potential of miRNAs in serum, plasma or CSF as diagnostic biomarkers for FTD and ALS, 9 17–20 focussing on comparing healthy controls and patients. However, our findings differ from preceding results: only two miRNAs from our signature (miR-345-5p and miR-200c-3p) were identified as differentially expressed in one of these studies, 20 none in the others. 17–19 Results are conflicting probably due to restricted choices for the analysed miRNAs 17 18 and heterogeneous cohorts, either with sporadic forms 18 19 or a mixture of sporadic and familial forms with different mutations.…”

“…Future work will explore longitudinal analyses of plasma miRNAs to assess their use as biomarkers of FTD and ALS progression. Grasso et al 2019 † 19 Magen et al 2020 † 20 This study †…”

“… 17–19 Results are conflicting probably due to restricted choices for the analysed miRNAs 17 18 and heterogeneous cohorts, either with sporadic forms 18 19 or a mixture of sporadic and familial forms with different mutations. 20 To the best of our knowledge, the present work is the first to compare the expression levels of plasma miRNAs between presymptomatic and symptomatic carriers focussing on C9orf72 mutation, in addition to providing a plasma miRNA signature that may contribute to the assessment of preclinical progression for C9orf72 -associated FTD and ALS. Table 4 displays a comparison among studies evaluating miRNAs from blood samples (serum or plasma) of patients with FTD and/or ALS.…”

“… 17 A wider miRNA profiling study 19 analysed 752 miRNAs, as a first attempt to perform an unbiased assessment of circulating miRNAs in patients with FTD. In addition, a more recent study 20 assessed the expression levels of 2313 miRNAs in a merged cohort of patients with FTD with different genetic forms ( C9orf72 , MAPT , GRN , TBK1 ) or with sporadic forms, by next generation RNA sequencing (RNA-seq). However, results among different studies have been conflicting so far, probably due to the heterogeneity of cohorts with respect to the underlying pathology (genetic or sporadic).…”

Muscle microRNAs in the cerebrospinal fluid predict clinical response to nusinersen therapy in type II and type III spinal muscular atrophy patients

“…On the basis of understanding the miRNA role in motor neuron diseases [11][12][13] and potential discovery of novel biomarkers [20][21][22] , we sought to test the utility of specific miRNAs in the cerebrospinal fluid (CSF) as candidate molecules to predict a positive clinical response to nusinersen in type II/III SMA patients.…”