Neurofilament Proteins Show Promise as Biomarkers of Neurodegeneration in FA

Neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH) — two key components of axons (nerve cell extensions responsible for transmitting nerve signals) — show promise as biomarkers of neurodegeneration in Friedrich’s ataxia (FA), a study reports.

The study, “NfL and pNfH are increased in Friedreich’s ataxia,” was published in the Journal of Neurology.

FA is a rare, inherited neuronal disorder in which defective copies of the frataxin gene (FXN) lead to the progressive loss of motor control (ataxia).

Neurons die over the course of the disease and neurofilaments — proteins that support axons — are thought to be released into the cerebrospinal fluid (CSF, the fluid that circulates in the brain and spinal cord), and blood.

NfL and pNfH are two axonal proteins that recently have been found at high levels in CSF samples of patients with different types of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), raising the possibility that both also may be useful biomarkers of neurodegeneration in FA.

Because frataxin is considered the main culprit in FA, studies tend to focus on assessing its levels as a measure of treatment success.

“However, serum markers reflecting the degenerative aspects of the disease are missing,” investigators wrote.

To evaluate their potential as FA biomarkers, researchers measured and compared NfL serum levels of 99 FA patients, ages 16–68, to those of 30 healthy individuals (controls). Serum levels of pNfH were measured and compared in a subgroup of 20 patients and nine controls.

Compared to controls, the levels of both NfL (median of 21.2 pg/ml versus 26.1 pg/ml) and pNfH (median of 23.5 pg/ml versus 92 pg/ml) were significantly higher among FA patients.

Furthermore, investigators found the levels of NfL varied by age among healthy individuals, but not among those with FA. Among controls, NfL serum levels rose in those age 30–50, and steeply increased in those age 50–65. In contrast, researchers did not see such an age dependency of NfL levels among those with FA.

The steady rise in serum levels among control subjects reached levels comparable to patients with FA at later ages. This meant that younger subjects could be classified easily as either healthy or sick, while middle-aged subjects could be classified moderately well. However, at the older age range, the distinction between healthy and sick individuals fell to little better than random.

In patients with FA, serum NfL levels were increased regardless of disease severity (assessed using the Scale for the Assessment and Rating of Ataxia, or SARA), its duration, and age of onset.

Serum pNfH levels also showed no correlation with disease severity or age. In fact, pNfH levels tended to be lower among those with a more severe disease, although this trend was not deemed statistically significant.

On average, serum NfL levels remained stable for a two-year period, as measured in 14 patients. Although individual levels varied slightly, no significant change was seen in the group as a whole.

The study opens new avenues for research into FA. It will be useful to understand, for instance, why NfL levels do not increase with age among those with FA. It is unknown whether this is caused by a decrease in neurodegeneration, or by higher mortality among those with more advanced disease.

Understanding this will likely reveal if NfL can be used to gauge neurodegeneration in older patients. Future studies also are needed to address how NfL and pNfH levels vary over time intervals longer than two years, and in patients younger than 16.

“Our study proposes neurofilaments as potential biomarkers for the assessment of neurodegeneration in interventional trials that aim to slow down disease activity in Friedreich’s ataxia,” researchers wrote.