Four miRNAs are differentially expressed in plasma between C9orf72-associated clinical conditions

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are increasingly recognised as constituting a spectrum of neurodegenerative disease. The C9orf72 intronic hexanucleotide repeat expansion is the most common genetic cause of FTD and ALS, accounting for about 1 in 10 of all cases, respectively.1 Though limited treatment options can provide a marginally decreased rate of disease progression, there is no current treatment that effectively halts neurodegeneration. However, recent advances have contributed to the development of antisense oligonucleotides targeting the C9orf72 repeat expansion with promising preliminary results.2

As we continue to elucidate the genetic basis of disease for FTD and ALS and progress towards therapeutic development, it is important to identify biomarkers to assess disease onset and progression, especially for presymptomatic or early-stage patients in whom potential disease-modifying treatments could prevent occurrence or worsening of disease. Serum-based biomarkers are an attractive, relatively non-invasive option, and recent studies have shown that expression levels of circulating microRNA (miRNA) may allow classification of disease type and progression for FTD and ALS.3–6

Kmetzsch and colleagues report a signature of four miRNAs that are differentially expressed in plasma between C9orf72-associated clinical conditions.7 To do this, the authors examined plasma expression levels of 2576 miRNAs obtained from 22 C9orf72 patients, 45 presymptomatic C9orf72 mutation carriers and 43 control individuals in the ongoing prospective PREV-DEMALS study. Of the 589 miRNAs remaining above noise level after differential expression analysis, miR-34a-5p and miR-345–5 p were significantly overexpressed in patients compared with healthy controls, while miR-200c-3p and miR-10a-3p were underexpressed. Interestingly, of the two miRNAs overexpressed in patients versus controls, miR-34a-5p was also significantly overexpressed in presymptomatic mutation carriers versus controls. MiR-345-5 p remained overexpressed in patients as compared with presymptomatic carriers. Together, this pattern of miRNA expression may provide an indication of disease stage, in addition to C9orf72 mutation status.

This study is novel in several aspects, including the application of next-generation RNA sequencing to analyse a large number of circulating miRNAs, the focus on FTD and ALS patients with an underlying C9orf72 repeat expansion, and the evaluation of presymptomatic as well as transitional stage subjects. Notably, the authors have used their miRNA expression signature to create binary classification models for clinical status and attempted to address the absence of a replication cohort through the use of their generalisation analysis. However, this secondary analysis revealed a weaker prediction performance, highlighting the need for follow-up with larger independent C9orf72 patient cohorts. Additionally, as the authors note, several of the components of their miRNA signature are also dysregulated in other neurodegenerative diseases, which limits their use as a standalone diagnostic tool but may not detract from their use in longitudinal disease monitoring especially when combined with other biomarkers and in the correct clinical context. Aside from our cautious optimism regarding the use of these four miRNAs as biomarkers of clinical progression in C9orf72-associated disease, these results also provide an additional motivation to investigate the role of their dysregulation in C9orf72 pathogenesis.