sNfL Levels Detect Neuronal Damage and Measure Treatment Effect in Hereditary Transthyretin Amyloidosis
—The use of serum neurofilament light chain was investigated for the detection of neuronal damage prior to polyneuropathy development in carriers and patients with hereditary transthyretin amyloidosis. In carriers who developed polyneuropathy, serum neurofilament light chain increased prior to symptom onset.
Serum neurofilament light chain (sNfL) levels can be used to detect neuronal damage prior to onset, for confirmation of polyneuropathy symptoms onset, and to monitor treatment effects in patients with hereditary transthyretin (ATTRv) amyloidosis, a recent study suggests.1
“In this retrospective longitudinal study, levels of sNfL in TTRv carriers and symptomatic ATTRv amyloidosis patients on treatment were measured to assess whether sNfL can detect neuronal damage before polyneuropathy can be detected by clinical assessments or NCS and to assess whether sNfL is a suitable biomarker to monitor treatment effect,” co-first authors Milou Berends, MD, and Anne F. Brunger, MD, from University Medical Center Groningen in Groningen, The Netherlands, and colleagues, noted in their article published in Amyloid.1
Study design and population
This retrospective study included asymptomatic TTRv carriers and ATTRv amyloidosis patients who attended a single center between January 1, 2000, and December 1, 2021. Of the 204 patients assessed, some were excluded based on receipt of a liver transplant, a concomitant disorder associated with neuronal damage, clinical trial participation, inconsistent NCS results, ATTRv cardiomyopathy without polyneuropathy, or if follow-up samples were not available. In total, 65 patients were selected for inclusion.1
Patients and carriers were classified into 1 of 3 groups, including those who were persistently asymptomatic (TTRv carriers, n=12; ATTRv amyloidosis patients, n=8), TTRv carriers who developed polyneuropathy and progressed to patients with symptomatic ATTRv amyloidosis (n=7), and ATTRv amyloidosis patients with polyneuropathy who received treatment with a TTR-stabilizer (n=20), a TTR-silencer (n=7), or both a TTR-silencer and a TTR-stabilizer (n=11).1
Over an average follow-up of 126 months, NT-proBNP increased in TTRv carriers who developed polyneuropathy. Over an average follow-up of 25 months, among ATTRv patients with polyneuropathy who were on a TTR-stabiliser, NT-proBNP increased and troponin T decreased.1
Assessment of sNfL levels by group
Among the 20 persistently asymptomatic TTRv carriers and ATTRv patients, a median increase in sNfL of 0.1 pg/mL/month was observed over an average follow-up of 26 months. The sNfL levels did not increase in 12 persistently asymptomatic TTRv carriers who did not have subcutaneous amyloid deposition, whereas median sNfL levels increased in the 8 persistently asymptomatic ATTRv patients. The monthly change in sNfL was higher in the ATTRv patients than in the TTRv carriers (0.2 pg/mL/month vs 0 pg/mL/month).1
Among the 7 TTRv carriers who developed polyneuropathy, median sNfL levels significantly increased after an average follow-up of 126 months, from 8.4 to 49.8 pg/mL until the first polyneuropathy disability score of 1, corresponding with a monthly change in sNfL of 0.3 pg/mL/month. In 5 patients, disease development and the course of the sNfL levels were correlated, whereas unexplained sNfL levels were observed in the other 2 patients.1
Among the 20 ATTRv patients with polyneuropathy who were treated with a TTR-stabilizer, no change in median sNfL was observed over an average follow-up of 25 months. Among the 18 patients treated with a TTR-silencer, there was a decrease in median sNfL over an average follow-up of 14 months, from 61.2 to 37.7 pg/mL. The monthly median change in sNfL was significantly different between those treated with a TTR-silencer versus a TTR-stabilizer (-1.4 vs -0.1 pg/mL/month; P<0.01).1
No difference in monthly change in sNfL was observed between patients treated with a TTR-silencer with or without concomitant treatment with a TTR-stabilizer.1
At the first time point where sNfL levels were assessed, ATTRv patients with polyneuropathy had higher levels of sNfL, regardless of treatment, compared with those who were persistently asymptomatic and the TTRv carriers who developed polyneuropathy. Additionally, no difference was observed between those who were persistently asymptomatic and the TTRv carriers who later developed polyneuropathy; however, at the last polyneuropathy disability assessment with a score of 0, those who later developed polyneuropathy had higher levels than those who were persistently asymptomatic (29.1 pg/mL vs 8.7 pg/mL).1
A higher monthly change in sNfL was seen for TTRv carriers who developed polyneuropathy between the last polyneuropathy disability assessment with a score of 0 and the first with a score of 1 compared with the change seen in those who were persistently asymptomatic. No difference in the monthly change in sNfL was seen between TTRv carriers who developed polyneuropathy and those who were persistently asymptomatic.1
Conclusions
In this study, the authors demonstrated the potential use of sNfL levels for the detection of neuronal damage prior to the onset of polyneuropathy symptoms and to monitor treatment effect in ATTRv amyloidosis patients.1 Furthermore, these findings support previous results that revealed increased sNfL levels in ATTRv patients with polyneuropathy.2-4
Limitations of this study include the retrospective nature of the study, the small cohort of TTRv carriers that developed polyneuropathy, and the differences in follow-up time in the different groups.1
“Our data support the use of sNfL in screening TTRv carriers and in monitoring disease progression and effect of treatment in ATTRv amyloidosis patients,” the authors concluded in Amyloid. “Larger studies are warranted to confirm and specify the results presented here and to investigate sNfL in relation to small fiber neuropathy, autonomic neuropathy and genotype.”1
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References
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