Protein changes may help track Friedreich’s ataxia disease activity
Patients show distinct changes in levels of NfL and tau in their blood
People with Friedreich’s ataxia (FA) show distinct changes in the blood proteins neurofilament light chain (NfL) and tau that could help track the disease and measure the effects of treatment, a study finds.
In younger patients, NfL levels were sharply higher than in healthy people, making it a promising early biomarker. But, unlike in most brain diseases, NfL levels in FA fell with age, approaching normal values by around age 40. Tau, however, remained consistently elevated across all ages, possibly reflecting its deeper role in the disease processes. The study, “Increase of Plasma Biomarkers in Friedreich’s Ataxia: Potential Insights into Disease Pathology,” was published in Movement Disorders.
FA is a genetic disorder that damages nerve cells, especially in the brain and spinal cord, or central nervous system. The damage is most severe in parts of the spinal cord that help control movement, leading to problems with coordination, balance, and other symptoms.
The disease lacks reliable, easy-to-measure biomarkers, that is, objective signs of disease that can be tracked over time. Such markers are crucial for clinical trials, as changes can signal if a treatment is working. Blood-based biomarkers are especially valuable in FA because certain proteins released from damaged nerve and support cells in the central nervous system can cross into the bloodstream. Measuring these proteins offers a window into ongoing nerve damage and disease activity without the need for invasive procedures.
“There is a growing need to identify robust and accessible biomarkers to monitor disease activity and therapeutic efficacy in [FA], especially given the recent advancements in this field,” the researchers wrote.
Emerging value of NfL and tau in FA
Different proteins have emerged as promising biomarkers for nerve cells damage, or neurodegeneration. These include NfL, a neuron-specific structural protein, and tau, a protein in nerve cells.
NfL is an established biomarker in multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). When neurons are damaged, and, to a lesser extent, during normal cell turnover, NfL is released into the surrounding fluid and can be measured in the cerebrospinal fluid (CSF), which surrounds the brain and spinal cord, and blood.
Tau helps maintain the stability and function of neurons, but in many neurodegenerative disorders it becomes abnormal. Elevated levels of tau in the blood may reflect this kind of functional alteration, signaling ongoing nerve cell injury and underlying disease processes.
The researchers earlier found evidence of elevated levels of NfL, but not total tau (t-tau), in a small group of FA patients. This study expands on these findings from two FA natural history studies (NCT02069509 and NCT03090789) that included “participants of different geographical origin and with a larger range of age at symptom onset,” wrote the researchers, who analyzed blood samples from 187 people with FA (median age, 31) who’d had the disease a median of 15 years. They also looked at samples from 127 healthy people in the U.K., who served as controls.
Differences in blood proteins
As in their previous work, the researchers saw elevated levels of NfL in the FA patients and were able to statistically differentiate between patients and control under the age of 20 with 100% accuracy. These differences weren’t as pronounced in older individuals, however. “NfL is a sensitive biomarker in early [FA], but decreases with age, converging with control values after 35-40 years,” they wrote.
This pattern of decreasing NfL until about age 40 seems to be unique to FA. In healthy people and other neurodegenerative disorders, NfL tends to increase over time, with bigger changes in older age. This decrease may reflect a gradual loss of the nerve fibers that produce NfL, meaning less protein is available for release into the blood, said the researchers, who noted other factors may also contribute, such as changes in disease mechanisms with age or differences in neurodevelopmental processes that persist into adulthood.
T-tau levels were also higher in the FA group, although the differences were smaller than those seen for NfL. This contradicted the previous findings, which showed t-tau was comparable between groups. “Elevated tau levels suggest involvement in underlying disease [processes],” the researchers wrote.
While t-tau stayed relatively constant over time in both groups, there was a slight decline over time in the FA group. Tau is a protein released when nerve fibers break down, but it can also be released during normal nerve cell turnover. Higher levels in FA may indicate the brain and spinal cord are trying to adapt to damage by rewiring and forming new connections.
Even with this age-related decline, however, t-tau levels in the FA group were still moderately elevated compared with controls across all age groups, which may suggest regenerative mechanisms in the CNS become exhausted over time.
Neither NfL nor t-tau showed a clear relationship with genetic correlates of disease severity or with the participants’ neurological status.
Other proteins involved in CNS neurodegeneration were also examined, but their levels weren’t significantly different between the groups. This may have been due in part to inconsistencies in measuring them. There did seem to be high levels of glial fibrillary acidic protein (GFAP) in younger FA patients, but without similarly aged controls, it was difficult to determine if this was meaningful. Marked elevation of NfL and, to a lesser extent, t-tau, indicates they might be useful as biomarkers, however.
“This could be a first step toward the use of NfL in clinical trials, in combination with functional outcomes,” to measure therapeutic effects, the researchers wrote, noting “this age-dependent pattern must be considered when interpreting the effect of interventions in clinical trials.”
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