BACKGROUND:
Whilst recent work has shown the potential of cerebrospinal fluid (CSF) biomarkers for frontotemporal dementia (FTD), less invasive plasma biomarkers are limited. We investigated plasma-derived extracellular vesicles (EVs) and analysed the synaptic protein neuronal pentraxin 1 (NPTX1). Previous work from our group identified mutation-associated NPTX1 changes in CSF from symptomatic genetic FTD carriers compared to non-carriers. The ability to measure peripheral NPTX1 changes in EVs, reflecting brain pathophysiology, offers potential for minimally invasive FTD fluid biomarkers.
METHODS:
We first developed a protocol to isolate EVs from human plasma via size exclusion chromatography, validating EV enrichment by western blot (CD9, flotillin-1, ApoB), and EV size and count by nanoparticle tracking analysis (NTA). Using a commercially available mesoscale discovery (MSD) platform kit, we then quantified the levels of NPTX1 in paired plasma and EV samples from a pilot cohort of 30 FTD mutation carriers (GRN, MAPT, C9orf72) and age- and sex-matched non-carrier controls from the GENetic FTD Initiative.
RESULTS:
Preliminary investigation first confirmed reliable detection of NPTX1 in plasma-derived EVs, and suggested it is contained within EVs. Analysis of plasma-derived EVs in the pilot cohort found no significant differences in EV size (p=0.197) or NPTX1/particle (p=0.339) between FTD mutation carriers and controls, or between specific mutation carrier groups (p=0.719, 0.727 respectively). Plasma NPTX1 similarly showed no group differences (carriers vs. non-carriers p=0.998, between mutation carrier groups p=0.806), but was significantly higher than paired EV NPTX1/particle for all individuals (p<2.2e-16).
CONCLUSION:
Our findings support the feasibility of measuring synaptic proteins in plasma-derived EVs and highlight their potential for minimally invasive biomarkers in genetic FTD with the appropriate lysis conditions. Our next steps will be to refine our approach to target brain-derived EVs from plasma, and further investigate FTD mutation-associated differences in a larger cohort. This work may offer new insight into early synaptic changes and aid in future biomarker development.