Early NfL blood levels differ in idiopathic and LRRK2 Parkinson’s

With disease mutation, marker of nerve cell damage slower to start rising

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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People with idiopathic Parkinson’s disease have significantly higher blood levels of neurofilament light chain (NfL) — a biomarker of nerve cell damage — than those whose Parkinson’s is associated with mutations in the LRRK2 gene, a study showed.

This difference, however, held true only for the early stages of disease, when blood NfL levels of people with LRRK2-related Parkinson’s very closely matched those of healthy adults. In later stages, no major differences were detected between the two patient groups.

Blood NfL levels, as such, “might be a more accurate biomarker to distinguish iPD [idiopathic, or unknown cause, Parkinson’s disease] from healthy subjects rather than all PD patients or LRRK2-PD from healthy subjects at the early stages,” the researchers wrote.

The study, “Serum neurofilament light chain in LRRK2 related Parkinson’s disease: A five years follow-up,” was published in the Journal of Clinical Neuroscience.

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Rising neurofilament light chain levels linked to Parkinson’s progression

It can be difficult to diagnose Parkinson’s in its early stages, when its symptoms can be similar to those of other conditions. There is currently no definite diagnostic test for the disease.

Neurofilament light chain is a major subunit of neurofilaments, key structural proteins of neurons. When nerve cell fibers are damaged and neurons die, neurofilaments are released into the bloodstream, making them a blood biomarker of nerve cell damage and death.

In Parkinson’s patients, previous studies have shown that higher NfL levels are associated with more severe motor symptoms and greater cognitive decline over time.

However, whether and how blood NfL levels change in people with Parkinson’s linked to mutations in the LRRK2 gene, one of the most common genetic causes of the disease, is not known.

“Finding a useful indicator with prominent … diagnostic value of neurodegenerative disorders would be invaluable for reaching an individual therapeutic decision, measuring drug effects in clinical trials, and facilitating earlier detection of PD in LRRK2 mutation carriers and slow disease progression,” the researchers wrote.

A team of researchers in Iran analyzed blood NfL levels in 103 people with LRRK2-associated Parkinson’s, 228 people with idiopathic Parkinson’s, and 176 healthy people of similar age and sex.

All were participating in the Parkinson’s Progression Markers Initiative, a longitudinal, observational study of people with and without Parkinson’s. All patients had early stage disease and were not on standard Parkinson’s treatments. Mean ages were 61.5 years for the LRRK2-PD group, 63.1 for the iPD group, and 61.5 for the control group of healthy adults.

Blood NFL levels were compared among the three groups at study’s start (baseline), and again at six-month, one-year, two-year, three-year, and five-year visits.

Neuronal damage may start earlier in idiopathic than LRRK2 patients

At baseline, higher blood NfL levels were significantly associated with older age and more severe motor disability — as assessed with the Movement Disorder Society Unified Parkinson’s Disease Rating Scale parts 2 and 3 — in all three groups.

Among Parkinson’s patients, higher NfL levels were significantly linked to poorer cognitive function, as measured with the Montreal Cognitive Assessment.

Significant differences in blood NfL levels also were detected among the three groups at baseline and at two, three, and five years. At baseline, NfL levels of LRRK2-PD patients were significantly lower than in iPD patients, but similar to those of healthy controls.

Over the study’s five follow-up years, blood NfL levels remained largely stable in healthy people, while they rose significantly in both groups of Parkinson’s patients.

In people with LRRK2-associated Parkinson’s, NfL levels began to differ from those of healthy controls at six months. From then up to year five, no significant difference in NfL levels was evident between the two groups of Parkinson’s patients.

These findings suggest that “neuronal damage in the initial stages of the disease is much higher in iPD compared to LRRK2-PD patients,” the researchers wrote.

Supporting this, a 2018 published study reported “a slower rate of both motor and cognitive impairment progression” among LRRK2-PD patients relative to those with idiopathic disease, they added.

“Measuring NFL [blood] levels may be a potential tool for differentiating LRKK2-PD and iPD patients at the very early stages but not in the following stages as the disease [progresses],” the researchers wrote.

It can also be used to help distinguish healthy people from those with idiopathic Parkinson’s and other neurodegenerative diseases linked to higher blood NfL levels.