Circulating brain-enriched microRNAs as novel biomarkers for detection and differentiation of neurodegenerative diseases

Abstract

BackgroundMinimally invasive specific biomarkers of neurodegenerative diseases (NDs) would facilitate patient selection and disease progression monitoring. We describe the assessment of circulating brain-enriched microRNAs as potential biomarkers for Alzheimer’s disease (AD), frontotemporal dementia (FTD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).MethodsIn this case-control study, the plasma samples were collected from 250 research participants with a clinical diagnosis of AD, FTD, PD, and ALS, as well as from age- and sex-matched control subjects (n = 50 for each group), recruited from 2003 to 2015 at the University of Pennsylvania Health System, including the Alzheimer’s Disease Center, the Parkinson’s Disease and Movement Disorders Center, the Frontotemporal Degeneration Center, and the Amyotrophic Lateral Sclerosis Clinic. Each group was randomly divided into training and confirmation sets of equal size. To evaluate the potential of circulating microRNAs enriched in specific brain regions affected by NDs and present in synapses as biomarkers of NDs, the levels of 37 brain-enriched and inflammation-associated microRNAs in the plasma of all participants were measured using individual qRT-PCR. A “microRNA pair” approach was used for data normalization.ResultsMicroRNA pairs and their combinations (classifiers) capable of differentiating NDs from control and from each other were defined using independently and jointly analyzed training and confirmation datasets. AD, PD, FTD, and ALS are differentiated from control with accuracy of 0.89, 0.90, 0.88, and 0.83 (AUCs, 0.96, 0.96, 0.94, and 0.93), respectively; NDs are differentiated from each other with accuracy ranging from 0.77 (AUC, 0.87) for AD vs. FTD to 0.93 (AUC, 0.98) for AD vs. ALS. The data further indicate sex dependence of some microRNA markers. The average increase in accuracy in distinguishing ND from control for all and male/female groups is 0.06; the largest increase is for ALS, from 0.83 for all participants to 0.92/0.98 for male/female participants.ConclusionsThe work presented here suggests the possibility of developing microRNA-based diagnostics for detection and differentiation of NDs. Larger multicenter clinical studies are needed to further evaluate circulating brain-enriched microRNAs as biomarkers for NDs and to investigate their association with other ND biomarkers in clinical trial settings.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-017-0316-0) contains supplementary material, which is available to authorized users.

Circulating miR-127-3p as a Potential Biomarker for Differential Diagnosis in Frontotemporal Dementia

“…They found that miR-29c-3p and miR-15a-5p had the highest classification accuracies separately, and by combing them in a simple ratio model (RELmiR-29c-3p/RELmiR-15a-5p), they found that AD patients could be distinguished from patients with other types of dementia (cut-off value 0.92) with a sensitivity of 90% and a specificity of 100% [56]. In another work investigating the assessment of circulating brain-enriched miRNAs as potential biomarkers for AD, FTD, PD, and amyotrophic lateral sclerosis (ALS), the authors revealed miRNA classifiers capable of differentiating NDs from each other with accuracy ranging from 0.77 (AUC, 0.87) for AD vs FTD to 0.93 (AUC, 0.98) for AD vs ALS [57]. Moreover, Vallelunga and colleagues, identified three up-regulated miRNAs in serum of MSA patients (miR-24, miR-34b, miR-148b) in comparison to PD patients [58].…”

“…Sheinerman and colleagues revealed sex dependence of certain brain-enriched miRNAs, which distinguished NDs from HC in sex-specific subsets with a significantly higher accuracy than in the total (female and male) population [57]. In another study, Denk and colleagues described gender specific differences concerning miR-106a, miR-17, miR-320, miR-19a, miR-221, miR-532, miR-95 in CSF of AD patients [62].…”

Circulating RNAs as Potential Biomarkers in Amyotrophic Lateral Sclerosis

“…MicroRNA pairs and their combinations could differentiate all diseases from controls and from each other with high accuracy. Up-regulation of pairs miR-206/miR-338-3p, miR9*/miR-129-3p and miR-335-5p/miR-338-3p differentiated ALS from controls, while combinations miR-31/miR-206, miR-125b/miR-335-5p and miR-107/miR-491-5p differentiated ALS from AD, respectively [121].…”

“…miR-338-3p is another potential circulating miRNA for ALS, since it was found consistently upregulated in several studies [45,50,111,114,121,126]. Its role as a functional miRNA in controlling different molecular pathways has been reported.…”

Sex as a biological variable in the pathology and pharmacology of neurodegenerative and neurovascular diseases

“…Mechanisms of sex differences in neurodegenerative and neurovascular pathologies. Reference key: 1 (Corder et al, ), 2 (Chauhan et al, ), 3 (Selvamani, Sathyan, Miranda, & Sohrabji, ; Kaidonis, Rao, Ouyang, & Stary, ), 4 (Sheinerman et al, ), 5 (Villa et al, ), 6 (Sarlus & Heneka, ), 7 (Rhodes, O'Toole, Wright, Czambel, & Rubin, ), 8 (Wickens, Bangasser, & Briand, ), 9 (Beeri et al, ), 10 (Maki, ), 11 (Paoletti et al, ), 12 (Lee et al, ), 13 (Scacchi, Gambina, Broggio, & Corbo, ), 14 (Roy‐O'Reilly & McCullough, ), 15 (Miller et al, ; Bushnell et al, ), 16 (Emdin et al, ), 17 (Selvamani et al, ), 18 (Giedd, Raznahan, Mills, & Lenroot, ), 19 (Giedd et al, ), and 20 (Giedd et al, )…”