Specific serum and CSF microRNA profiles distinguish sporadic behavioural variant of frontotemporal dementia compared with Alzheimer patients and cognitively healthy controls

PLoS One. 2018 May 10;13(5):e0197329. doi: 10.1371/journal.pone.0197329. eCollection 2018.

Abstract

Information on circulating miRNAs in frontotemporal lobar degeneration is very limited and conflicting results have complicated an interpretation in Alzheimer's disease thus far. In the present study we I) collected samples from multiple clinical centers across Germany, II) defined 3 homogenous patient groups with high sample sizes (bvFTD n = 48, AD n = 48 and cognitively healthy controls n = 44), III) compared expression levels in both CSF and serum samples and IV) detected a limited set of miRNAs by using a MIQE compliant protocol based on SYBR-green miRCURY assays that have proven reliable to generate reproducible results. We included several quality controls that identified and reduced technical variation to increase the reliability of our data. We showed that the expression levels of circulating miRNAs measured in CSF did not correlate with levels in serum. Using cluster analysis we found expression pattern in serum that, in part, reflects the genomic organization and affiliation to a specific miRNA family and that were specifically altered in bvFTD, AD, and control groups. Applying factor analysis we identified a 3-factor model characterized by a miRNA signature that explained 80% of the variance classifying healthy controls with 97%, bvFTD with 77% and AD with 72% accuracy. MANOVA confirmed signals like miR-320a and miR-26b-5p at BH corrected significance that contributed most to discriminate bvFTD cases with 96% sensitivity and 90% specificity and AD cases with 89% sensitivity and specificity compared to healthy controls, respectively. Correlation analysis revealed that miRNAs from the 3-factor model also correlated with levels of protein biomarker amyloid-beta1-42 and phosphorylated neurofilament heavy chain, indicating their potential role in the monitoring of progressive neuronal degeneration. Our data show that miRNAs can be reproducibly measured in serum and CSF without pre-amplification and that serum includes higher expressed signals that demonstrate an overall better ability to classify bvFTD, AD and healthy controls compared to signals detected in CSF.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease / blood*
  • Alzheimer Disease / cerebrospinal fluid*
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Biomarkers / blood
  • Biomarkers / cerebrospinal fluid
  • Cluster Analysis
  • Diagnosis, Differential
  • Factor Analysis, Statistical
  • Female
  • Frontotemporal Dementia / blood*
  • Frontotemporal Dementia / cerebrospinal fluid*
  • Humans
  • Male
  • MicroRNAs / blood*
  • MicroRNAs / cerebrospinal fluid*
  • Middle Aged
  • Neurofilament Proteins / cerebrospinal fluid
  • Peptide Fragments / cerebrospinal fluid
  • Reproducibility of Results

Substances

  • Amyloid beta-Peptides
  • Biomarkers
  • MicroRNAs
  • Neurofilament Proteins
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • neurofilament protein L

Grants and funding

The study was supported by grants from the German Federal Ministry of Education and Research (project: FTLDc 01GI1007A), the JPND network PreFrontAls (01ED1512), the EU (FAIR-PARK II 633190), the German Research Foundation/DFG (SFB1279), the foundation of the state Baden-Württemberg (D.3830), Boehringer Ingelheim Ulm University BioCenter (D.5009) and the Thierry Latran Foundation. The work of A.E.V was funded by the Deutsche Forschungsgemeinschaft (DFG, VO 2028/1-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.