NfL levels may mediate link between dementia, LRRK2 variants

Change in NfL levels over time may predict dementia in LRRK2-linked disease

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Scientists have discovered that long-term changes in a biomarker of nerve damage, called neurofilament light chain (NfL), could be used to predict cognitive decline in people with Parkinson’s disease due to certain mutations.

They found that a slower progression of dementia in people with LRRK2-associated Parkinson’s compared with those who have idiopathic (of unknown cause) disease could be partially attributed to slower increases in NfL.

In an analysis of Parkinson’s patients with various disease-associated mutations or those with idiopathic disease, researchers found that patients with SNCA mutations had the fastest change in NfL levels over time, whereas those with LRRK2 mutations had the slowest and were at a decreased risk of developing dementia, which was mediated by the change in NfL levels over time. While SNCA-Parkinson’s patients were at an elevated risk of dementia, it did not appear to be mediated by NfL levels.

“These findings provide insights into the potential utility of dynamic NfL in predicting cognitive decline in [Parkinson’s disease] and the underlying mechanisms of how specific mutations might influence disease progression,” researchers wrote.

The study, “Neurofilament light chain as a mediator between LRRK2 mutation and dementia in Parkinson’s disease,” was published in npj Parkinson’s Disease.

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Cognitive problems are common in Parkinson’s

Cognitive impairments are common in Parkinson’s patients, and may progress from mild difficulties to dementia — defined as cognitive problems that interfere with daily functioning — over the course of the disease.

Efforts are underway to identify biomarkers for predicting the progression of these cognitive declines. One such potential biomarker is NfL, the levels of which have been correlated with motor and cognitive impairments in people with idiopathic Parkinson’s disease.

Moreover, the change in NfL over time has been identified as a possible biomarker to predict cognitive declines and dementia risk.

Still, the potential role of NfL in people with Parkinson’s associated with certain genetic mutations has not been fully explored.

These genetic factors, including mutations in the LRRK2, GBA, and SNCA genes work via different mechanisms to drive Parkinson’s progression. Each can have different effects on cognitive trajectories; while LRRK2 has been linked to a milder cognitive profile, both GBA and SNCA are associated with more severe cognitive impairments.

“However, it remains unclear whether NfL plays a mediating role in the association between these mutations and cognitive decline,” the researchers wrote.

These findings provide insights into the potential utility of dynamic NfL in predicting cognitive decline in [Parkinson’s disease] and the underlying mechanisms of how specific mutations might influence disease progression.

In their study, a team of scientists in China aimed to investigate whether NfL levels differ between Parkinson’s patients with different types of mutations over time, and whether NfL is linked to the development of dementia in these groups.

Their analysis involved 184 healthy people and 617 Parkinson’s patients involved in the Parkinson’s Progression Markers Initiative, a large international study led by the Michael J. Fox Foundation for Parkinson’s Research.

Of the Parkinson’s patients, 142 had LRRK2 mutations, 76 had GBA mutations, 18 had SNCA mutations, and 381 had idiopathic Parkinson’s.

Overall, Parkinson’s patients had significantly higher blood NfL levels than healthy people at the study’s start (baseline), as well as lower scores on tests of cognitive function.

Among the Parkinson’s subgroups, notable differences included lower cognitive scores in those with LRRK2 mutations compared with idiopathic disease. Patients with GBA mutations also exhibited signs of more advanced motor symptoms compared with idiopathic Parkinson’s patients.

After adjusting for age, sex, disease duration, and educational status to account for baseline differences between the groups, patients with SNCA mutations had significantly higher blood NfL levels than those with idiopathic Parkinson’s, but all other comparisons did not reach statistical significance.

Baseline blood NfL levels did not differ significantly between Parkinson’s patients with or without dementia.

Next, the scientists estimated the long-term trajectory of NfL levels in each group, finding that Parkinson’s-associated mutations had a significant impact on NfL changes over time. The SNCA group showed the highest estimated annual increase in NfL while those in the LRRK2 group had the lowest.

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Change in blood NfL levels linked to likelihood of dementia over time

Overall, a higher estimated change in blood NfL levels was associated with an increased likelihood of conversion to dementia over time. Still, baseline NfL levels were not associated significantly with dementia.

By specific mutation type, LRRK2 mutations were directly associated with a reduced risk of dementia, which was partly mediated by the estimated change in NfL for those patients.

SNCA mutations were found to be directly linked to a risk of dementia, but this was not mediated by NfL levels. GBA was not directly or indirectly associated with dementia risk.

Overall, “the findings of our study suggest that longitudinal changes in serum NfL levels differ among different [Parkinson’s disease] mutations,” the researchers wrote.

Still, the mechanisms that might underlie a link between mutations, NfL, and dementia are not clear.

“Indeed, future research is needed to explore the underlying pathology of mutation in dementia through NfL,” the researchers wrote.