A blood miRNA signature associates with sporadic Creutzfeldt-Jakob disease diagnosis

Abstract

Sporadic Creutzfeldt-Jakob disease (sCJD) presents as a rapidly progressive dementia which is usually fatal within six months. No clinical blood tests are available for diagnosis or disease monitoring. Here, we profile blood microRNA (miRNA) expression in sCJD. Sequencing of 57 sCJD patients, and healthy controls reveals differential expression of hsa-let-7i-5p, hsa-miR-16-5p, hsa-miR-93-5p and hsa-miR-106b-3p. Downregulation of hsa-let-7i-5p, hsa-miR-16-5p and hsa-miR-93-5p replicates in an independent cohort using quantitative PCR, with concomitant upregulation of four mRNA targets. Absence of correlation in cross-sectional analysis with clinical phenotypes parallels the lack of association between rate of decline in miRNA expression, and rate of disease progression in a longitudinal cohort of samples from 21 patients. Finally, the miRNA signature shows a high level of accuracy in discriminating sCJD from Alzheimer's disease. These findings highlight molecular alterations in the periphery in sCJD which provide information about differential diagnosis and improve mechanistic understanding of human prion diseases.

Distribution of microRNA profiles in pre-clinical and clinical forms of murine and human prion disease

“…The difference in the direction of expression may be due to the enrichment of disease-associated miRNAs in EVs compared to those found in whole blood and circulating serum 16 . Similar to the study performed by Norsworthy et al 44 , we did not find any correlation with miRNA expression and polymorphism subtypes. The enrichment of disease associated miRNAs causes an upregulation of miRNA compared to controls however, may be downregulated due to being diluted within the bloodstream when analysing non-EV samples.…”

“…Despite the inter-disease and species variability, pre-clinical miRNA candidates from this mouse model were demonstrated to classify sCJD subjects from a human clinical cohort with an AUC of 0.800. In comparison, Norsworthy et al performed miRNA profiling on whole blood samples collected from a cohort of sCJD patients which resulted identifying 3 miRNAs (hsa-let-7i-5p, hsa-miR-16-5p, hsa-miR-93-5p and hsa-miR-106b-3p) downregulated in sCJD and provided a combined AUC of 0.788 44 . In comparison, hsa-miR-16-5p was also found deregulated in our study however, upregulated in serum EVs of sCJD patients and pre-clinical M1000 infected mice.…”

“…The enrichment of disease associated miRNAs causes an upregulation of miRNA compared to controls however, may be downregulated due to being diluted within the bloodstream when analysing non-EV samples. Nonetheless, the above recent studies 43 , 44 show that there is interest in developing a blood-based test for sCJD, in particular, to screen suspected CJD cases. Combining the miRNA signatures found between our studies may help in refining a sCJD panel that can be applied to several cohorts and improve independent validation studies.…”

MicroRNAs in Prion Diseases—From Molecular Mechanisms to Insights in Translational Medicine

“…According to Norsworthy and colleagues (2020) [ 54 ], available blood tests are not able to discriminate sCJD from other neurodegenerative disorders, such as AD for example. Thus, they set out to investigate whether they could find a miRNA signature specific to sCJD in human blood samples.…”

“…Thus, they set out to investigate whether they could find a miRNA signature specific to sCJD in human blood samples. Using RNA sequencing, RT-qPCR, and two independent patient groups, they were able to validate the downregulation of three miRNAs (hsa-let-7i-5p, hsa-miR-16-5p, and hsa-miR-93-5p) and the upregulation of four of their targets (CCND3; CDKN1A; ZFP36; NAPL1L) [ 54 ]. They did not find any correlations of miRNA dysregulation with clinical parameters (age of onset, duration of disease, and MRC Scale score, for example) or disease progression.…”