MicroRNA signatures in genetic frontotemporal dementia and amyotrophic lateral sclerosis
Virgilio Kmetzsch1,2, Morwena Latouche3, Dario Saracino1,4,5
1Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, CNRS, Inria, Inserm, AP-HP, Hôpital de la Pitié Salpêtrière, F-75013, Paris, France.
Objective:
MicroRNAs are promising biomarkers of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), but discrepant results between studies have so far hampered their use in clinical trials. We aim to assess all previously identified circulating microRNA signatures as potential biomarkers of genetic FTD and/or ALS, using homogeneous, independent validation cohorts of C9orf72 and GRN mutation carriers.
Methods:
104 individuals carrying a C9orf72 or a GRN mutation, along with 31 controls, were recruited through the French research network on FTD/ALS. All subjects underwent blood sampling, from which circulating microRNAs were extracted. We measured differences in the expression levels of 65 microRNAs, selected from 15 published studies about FTD or ALS, between 31 controls, 17 C9orf72 presymptomatic subjects, and 29 C9orf72 patients. We also assessed differences in the expression levels of 30 microRNAs, selected from five studies about FTD, between 31 controls, 30 GRN presymptomatic subjects, and 28 GRN patients.
Results:
More than half (35/65) of the selected microRNAs were differentially expressed in the C9orf72 cohort, while only a small proportion (5/30) of microRNAs were differentially expressed in the GRN cohort. In multivariate analyses, only individuals in the C9orf72 cohort could be adequately classified (ROC AUC up to 0.98 for controls versus presymptomatic subjects, 0.94 for controls versus patients, and 0.77 for presymptomatic subjects versus patients) with some of the signatures.
Interpretation:
Our results suggest that previously identified microRNAs using sporadic or mixed cohorts of FTD and ALS patients could potentially serve as biomarkers of C9orf72-associated disease, but not GRN-associated disease.
Insights
Circulating microRNAs show potential as biomarkers for C9orf72-associated frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). However, these microRNA signatures are not effective for GRN-associated disease, indicating a need for gene-specific biomarker development.
Area of Science:
- Neuroscience
- Genetics
- Biomarker Discovery
Background:
- MicroRNAs are investigated as biomarkers for frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS).
- Previous studies show inconsistent results, hindering clinical trial application.
- Genetic mutations in C9orf72 and GRN are key causes of familial FTD/ALS.
Purpose of the Study:
- To validate previously identified circulating microRNA signatures as biomarkers for genetic FTD/ALS.
- To assess the utility of these signatures in independent cohorts of C9orf72 and GRN mutation carriers.
Main Methods:
- Analysis of 104 individuals with C9orf72 or GRN mutations and 31 controls.
- Extraction and measurement of circulating microRNAs from blood samples.
- Comparison of microRNA expression levels based on published signatures for C9orf72 and GRN cohorts.
Main Results:
- Over half of selected microRNAs were differentially expressed in the C9orf72 cohort (35/65).
- A small fraction of microRNAs showed differential expression in the GRN cohort (5/30).
- Multivariate analysis demonstrated effective classification of C9orf72 subjects using specific microRNA signatures (ROC AUC up to 0.98).
Conclusions:
- Circulating microRNAs may serve as biomarkers for C9orf72-associated FTD/ALS.
- These microRNA signatures are not suitable for GRN-associated FTD/ALS.
- Gene-specific biomarker strategies are necessary for different genetic forms of FTD/ALS.
