4 blood biomarkers may help predict LRRK2-associated Parkinson’s

Predicting disease onset is challenging due to lack of early progression biomarkers

Joana Vindeirinho, PhD avatar

by Joana Vindeirinho, PhD |

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Scientists have identified potential biomarkers for the early detection of Parkinson’s disease in certain people carrying a common disease mutation.

Specifically, they found that a combination of four small RNA molecules, called microRNAs (miRNAs), in the blood may help predict disease onset in people who carry a Parkinson’s-associated LRRK2 mutation and who show early signs of the disease in brain scans.

Also, among carriers of the mutation, called G2019S, changes in certain miRNA levels were higher before the onset of motor symptoms, but lessened after a diagnosis of LRRK2-associated Parkinson’s (L2PD).

“If validated, some of the identified miRNAs hold potential as early progression biomarkers or pheno-conversion [symptom onset] in premotor G2019S carriers. These findings may have implications for early PD [Parkinson’s disease] detection or early neuroprotective strategies when available,” researchers wrote.

The findings were published in a study, “Differential serum microRNAs in premotor LRRK2 G2019S carriers from Parkinson’s disease,” in the journal npj Parkinson’s Disease.

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G2019S mutation is the most commonly associated with Parkinson’s

Mutations in the LRRK2 gene are linked to a high risk of developing Parkinson’s and are one of the most frequent causes of sporadic and familial Parkinson’s. Among these, the G2019S mutation is the most commonly associated with the disease.

However, not all people carrying this variant end up developing Parkinson’s, and its associated risk varies across populations. As such, while G2019S carriers are at a higher Parkinson’s risk, “predicting disease onset is challenging due to the lack of early progression biomarkers,” the researchers wrote.

The use of miRNAs, small molecules that regulate the activity of other genes, as potential blood biomarkers has been proposed for several diseases, including Parkinson’s.

Now, a research team in Spain has assessed blood levels of miRNAs among 60 G2019S carriers at different stages of risk, including 20 diagnosed with L2PD, to identify miRNAs with the potential to be progression biomarkers.

The 40 carriers without motor symptoms were further separated by risk using DaT-SPECT, an imaging technique that can detect deficits in dopamine signaling in the brain, a hallmark of Parkinson’s disease.

Those with a normal test result were included in the lower risk, DaT-negative group, while those with reduced dopamine signaling were included in the higher risk, DaT-positive group. These pre-motor carriers were followed for about eight years, with clinical assessments conducted every two years on average.

The team also enrolled 19 people with idiopathic, or of unknown cause, Parkinson’s, and 40 healthy people as controls.

If validated, some of the identified miRNAs hold potential as early progression biomarkers or pheno-conversion [symptom onset] in premotor G2019S carriers. These findings may have implications for early PD [Parkinson’s disease] detection or early neuroprotective strategies when available.

Results showed that, of 2,578 miRNAs assessed, 21 in the DaT-negative group, 10 in the DaT-positive group, 11 in the L2PD group, and 45 in the idiopathic Parkinson’s group showed significantly different levels when compared with the control group.

Additionally, most of these candidate miRNAs were group-specific, with little overlap between groups.

“These results indicate that microRNA deregulation is more prominent in [idiopathic Parkinson’s] than in L2PD and that specific miRNA changes occur across the continuum of progression stages in [pre-motor] G2019S carriers including DaT-negative and DaT-positive,” the team wrote.

When looking specifically at 12 candidate miRNAs, the researchers found that eight of them showed significantly altered levels in one or more of the G2019S carrier groups relative to controls.

All eight had increased levels (up-regulated) in the DaT-negative group, six were up-regulated in the DaT-positive group, and one was up-regulated in the L2PD group. A few miRNA differences were also observed between two additional groups: 19 L2PD patients and 20 healthy controls.

Among the G2019S carrier groups, most miRNA changes were found between the DaT-positive group and the L2PD group. Modest differences were found between the DaT-negative and DaT-positive groups.

“These results support the concept of a progressive decline in the number of miRNAs deregulated across the successive progression stages in G2019S carriers,” the researchers wrote.

A comparison between blood samples taken at the start of the study and those taken four and eight years later showed significant changes over time in 11 of the 12 candidate miRNAs in the DaT-negative group and in 10 of the 12 in the DaT-positive group.

Five of these miRNAs showed consistent level changes at both timepoints, while others varied only at one of the timepoints. This indicated that “levels of miRNAs deregulated at PD premotor stages are dynamic and can vary across time, at least during the 8-year follow-up period of this study,” the team wrote.

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4 miRNAs with ‘reasonable discriminative power’ could be early biomarkers

To identify miRNA changes with potential as progression biomarkers, the researchers compared data between DaT-positive patients who did not develop Parkinson’s symptoms — or did not pheno-convert — during the study and those diagnosed with L2PD (including four DaT-positive patients who pheno-converted, or developed symptoms, during follow-up).

In this analysis, three miRNAs — miR-4505, miR-8069, and miR-6125 — were significantly associated with pheno-conversion or symptom onset. One other, miR-451a, also showed a link with increased risk of pheno-conversion, but it did not reach statistical significance.

Notably, when combined, these four miRNAs allowed the researchers to differentiate between G2019S carriers who pheno-converted and those who didn’t with a high level of accuracy.

“We identified 4 miRNAs with a reasonable discriminative power to discern pheno-converted vs. non-pheno-converted G2019S carriers, which hold promise as early progression biomarkers for L2PD,” the team wrote.

These miRNAs “could be prioritized in subsequent studies,” which should also have longer follow-up periods, the team added.