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MicroRNAs as biomarkers for nervous system disorders

Early detection of neurological conditions is challenging, but recent research suggests that to understand what is wrong in the brain, we should look in the blood.

The challenge for early diagnosis of most neurological and neurodegenerative conditions lies in the lack of available inexpensive and non-invasive methods of assessing specific molecular changes in the brain. MicroRNAs (miRNAs)—a class of small non-coding RNAs involved in gene regulation—may provide a step in the right direction.

Because miRNAs are highly expressed in the nervous system and are present and stable in extracellular fluid, they have great potential as biomarkers for diagnosis of disease states. Mounting evidence in recent literature suggests that miRNAs can indeed make ideal biomarkers for diagnosing diseases of the nervous system, as shown in a few examples below.


Alzheimer’s disease

Alzheimer's disease (AD) is the most common form of dementia, yet its diagnosis continues to pose a challenge because the only definitive way to diagnose AD is still by performing a histological examination after autopsy.

A recent study used genome-wide serum miRNA expression analysis by high-throughput screening in a patient cohort of over 200 AD patients to identify serum miRNA biomarkers for Alzheimer's disease (Tan et al., 2014). They detected six miRNAs that were significantly down-regulated in AD patients and distinguished them from healthy controls.

Among these, miR-342-3p displayed the highest sensitivity and specificity for disease duration and correlated well with the Mini-Mental State Examination score, which is used to clinically measure cognitive impairment. Whereas miR-342-3p has not been implicated in AD before, it is deregulated in many other human pathologies, including cancer and autoimmune diseases.

While further validation studies are needed in larger cohorts combined with other clinical parameters, miR-342-3p alone may prove useful as a non-invasive biomarker for AD diagnosis.


Autism

Autism spectrum disorders (ASD) encompass a group of neurodevelopmental disorders that affect various facets of behavior, including communication and social interactions. Estimates suggest that about 1 in 90 individuals has ASD.

A recent study examined the serum expression profiles of 125 neurologically relevant miRNAs in children with autism spectrum disorders who had never received drug treatment (Vasu et al., 2014). The authors detected a signature of thirteen differentially expressed miRNAs between ASD and control groups, with five miRNAs showing good potential as predictive biomarkers of ASD. 

The researchers performed miRNA profiling in postmortem brains and confirmed that two of the miRNAs, miR-181b-5p and miR-328, have expression changes consistent between both the brain and the blood. Although further studies are needed, these results suggest that serum miRNAs could be potential non-invasive biomarkers of ASD.


Schizophrenia

Circulating miRNAs have also been implicated as promising blood-based biomarkers for schizophrenia patients. In a sample of schizophrenic and control patients, miR-30e, miR-181b, miR-34a, miR-346 and miR-7 had significantly increased expression in patients with schizophrenia. These five miRNAs displayed significant specificity and selectivity as potentially useful biomarkers distinguishing schizophrenia patients (Sun et al., 2015).

Of these five miRNAs, miR-30e and miR-181b, and two other miRNAs, miR-132 and miR-432, significantly decreased in expression following pharmacological treatment. In terms of symptom improvement, the high-effect subgroup showed a significantly greater decrease in miR-132 and miR-432 plasma levels compared with the low-effect subgroup after a six-week treatment course.

Overall, the authors concluded that changes in the serum levels of miR-132, miR-181b, miR-30e and miR-432 were potentially indicative of symptom improvements, treatment responses and prognosis.

Circulating miRNAs as biomarkers of nervous system diseases

miRNAs play important roles in the transcriptional networks of the human brain, so it’s not surprising that changes in brain-specific miRNA expression would be indicative of many pathologies, depression and epilepsy among them. Liu et al. (2014) profiled plasma samples of patients with major depressive disorder (MDD) and identified miR-101-3p and miR-93-5p as top putative MDD biomarkers.

Similarly, Wang et al. (2015) measured the differences in expression of serum miRNAs between drug-resistant and drug-responsive patients with epilepsy to find that miR-301a-3p had the best sensitivity and specificity in distinguishing the drug-resistant group and was also negatively correlated with seizure severity (Wang et al., 2015).

Circulating miRNAs demonstrate stability in the serum and plasma and are able to cross the blood-brain barrier, thus holding great promise as non-invasive and quantitative biomarkers. To realize the full potential of miRNA biomarkers for nervous system diseases, tools are required for the routine analysis of miRNAs from a range of clinical samples.


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