Downregulation of exosomal miR-204-5p and miR-632 as a biomarker for FTD: a GENFI study

Abstract

Objective To determine whether exosomal microRNAs (miRNAs) in CSF of patients with FTD can serve as diagnostic biomarkers, we assessed miRNA expression in the Genetic FTD Initiative (GENFI) cohort and in sporadic FTD. Methods GENFI participants were either carriers of a pathogenic mutation in progranulin (GRN), chromosome 9 open reading frame 72 (C9orf72) or microtubule-associated protein tau (MAPT), or were at risk of carrying a mutation because a first-degree relative was a known symptomatic mutation carrier. Exosomes were isolated from CSF of 23 pre-symptomatic and 15 symptomatic mutation carriers, and 11 healthy non-mutation carriers. Expression of 752 miRNAs was measured using qPCR arrays and validated by qPCR using individual primers. MiRNAs found differentially expressed in symptomatic compared to pre-symptomatic mutation carriers were further evaluated in a cohort of 17 patients with sporadic FTD, 13 patients with sporadic Alzheimer’s disease (AD), and 10 healthy controls (HCs) of similar age. Results In the GENFI cohort, miR-204-5p and miR-632 were significantly decreased in symptomatic compared to pre-symptomatic mutation carriers. Decrease of miR-204-5p and miR-632 revealed receiver operator characteristics with an area of 0.89 [90% CI: 0.79–0.98] and 0.81 [90% CI: 0.68–0.93], respectively, and when combined an area of 0.93 [90% CI: 0.87–0.99]. In sporadic FTD, only miR-632 was significantly decreased compared to AD and HCs. Decrease of miR-632 revealed an area of 0.90 [90% CI: 0.81–0.98]. Conclusions Exosomal miR-204-5p and miR-632 have potential as diagnostic biomarkers for genetic FTD and miR-632 also for sporadic FTD.

Education modulates brain maintenance in presymptomatic frontotemporal dementia

“…Genetic FTD is preceded by a long period in which, despite the evidence of initial changes in biomarkers and brain structure, behaviour and cognition are spared. [17,[19][20][21] Pharmacological and non-pharmacological interventions may provide better clinical outcomes if applied in this phase, when the brain can still cope with pathology processes, and such treatments may eventually delay disease onset.…”

The roles of extracellular vesicle microRNAs in the central nervous system

“…Additionally, an in vitro model of prion disease identified at least 17 miRNAs that were dysregulated in EVs derived from prion‐infected neurons compared to uninfected neurons (Bellingham, Coleman, & Hill, ), while three miRNAs were upregulated in CSF EVs isolated from patients with acute encephalitis syndrome due to infection with Japanese Encephalitis virus (Goswami et al, ). Decreased EV‐packaged miR‐205‐5p and −632 was also recently observed in the CSF of individuals with symptomatic frontotemporal dementia, compared to presymptomatic and healthy controls (Schneider et al, ). Taken together, these studies provide potential clinical utility in using EV miRNA levels as clinically relevant biomarkers for a variety of CNS disorders.…”

MicroRNA sequencing of rat hippocampus and human biofluids identifies acute, chronic, focal and diffuse traumatic brain injuries

“…(2020) 10:3341 | https://doi.org/10.1038/s41598-020-60133-z www.nature.com/scientificreports www.nature.com/scientificreports/ function 21 . Notably, miR-204-5p which was downregulated in chronic TBI was also reported downregulated in frontotemporal dementia 22 , a finding that suggests that this miRNA might serve as a useful biomarker of early stage, subclinical dementia in neurodegenerative disorders. TBI-dysregulated miRNAs also regulate multiple genes involved in neurodevelopmental functions 23 ; Schork et al, showed in their study of shared risk across psychiatric disorders, that all share dysregulated expression of common gene variants that regulate neural development 24 .…”