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Among patients with hereditary transthyretin amyloid polyneuropathy (ATTRv-PN), serum neurofilament light chain (NfL) identifies conversion to symptomatic disease, a recent study suggests.¹

鈥淸T]he present series aimed to evaluate the use of serum NfL using the Simoa platform in a cohort of asymptomatic and symptomatic ATTRv gene carriers,鈥� Antonia S. Carroll, MBBS, FRACP, Brain and Mind Center, Faculty of Medicine and Health, Translational Research Collective University of Sydney and Department of Neurology, Royal Prince Alfred Hospital, Sydney, Australia, and colleagues noted in Amyloid.

NfL has been shown to be a potential biomarker of neuropathy in hereditary transthyretin amyloidosis (ATTRv), with increased levels observed in individuals with symptomatic neuropathy compared with healthy controls and asymptomatic carriers.^2-4

鈥淚n addition to validation of studies using a real-life cohort, NfL was assessed longitudinally to quantitate change over time, to propose appropriate NfL cutoff values for conversion to symptomatic disease and to evaluate change in NfL with treatment in a real-life cohort,鈥� the authors explained in Amyloid.

Participants

This study included 59 patients with a stored serum sample at the time of clinical review between 2015 and 2022 who had suspected or diagnosed neuropathy resulting from ATTRv amyloidosis or were asymptomatic carriers of a neuropathic variant. Of these, 26 patients had TTRT60A ATTRv mutations, 12 had TTRV30M, and 22 had other variants. No differences in baseline characteristics of the participants existed across the variant groups.¹

No correlation was found between log(NfL) and creatinine, estimated glomerular filtration rate (eGFR), or age. Furthermore, NfL was not significantly different between men and women or across the variant groups. These variables were thus excluded as covariates in subsequent analyses.¹

During functional assessment, baseline levels of NfL were correlated with the neuropathy impairment score (NIS) (P<.001) and the lower limb subset (P<.001), the Charcot-Marie-Tooth symptom subscore (P<0.001), the Charcot-Marie-Tooth symptom and examination score (P<.001), the Charcot-Marie-Tooth composite score of symptoms, signs, and neurophysiology (P<.001), and the Medical Research Council (MRC) score (P<0.001). No correlation was found between baseline NfL and the Norfolk quality of life diabetic neuropathy score (P<.001).¹

Baseline levels of NfL increased with disease severity, as demonstrated by significant differences in NfL levels between polyneuropathy disability (PND) score cohorts of PND0 and PND2 (P=.002), PND3A (P=.002) and PND3B (P=.003), and PND1 and PND3B (P=.047), as well as between Familial Amyloidosis Polyneuropathy (FAP) stage cohorts FAP2 and FAP0 (P<.001) and FAP 1 (P=.03). NfL levels >52.2 pg/mL were able to discriminate patients with PND2 and above from patients with PND0 and 1, with a specificity of 55.5% and a sensitivity of 100%.¹

NfL as a longitudinal disease marker

For 50 individuals, a total of 173 longitudinal pre- and post-treatment samples were available over a maximum of 4.75 years of follow-up. There were 121 pre-treatment samples from 43 individuals over an average of two years. For these analyses, the researchers identified four groups:

• Asymptomatic: no symptoms throughout the follow-up period with PND 0, MRC 70, and NIS 0
• Symptomatic: evidence of symptoms at baseline; NIS >5 OR MRC <70 and PND 鈮�1
• Sensory converters: asymptomatic at initial review; at follow-up transitioned from PND/FAP scores of 0 to 1, NIS 0 to >0, and maintained MRC score = 70
• Sensorimotor converters: asymptomatic at baseline; at follow-up converted from PND score of 0 or 1 to 鈮�2; developed muscle weakness (MRC <70)

At baseline, there were 27 asymptomatic and 16 symptomatic individuals. During follow-up, 11 remained asymptomatic, five converted to a sensorimotor neuropathy, 11 converted to sensory neuropathy, and 16 remained symptomatic.¹

No significant differences in age, gender, creatinine, or eGFR were observed according to disease progression groups. At baseline, significant differences among the disease progression groups were found for the NIS (P<.0001) and the lower limb subset (P<.0001), the Charcot-Marie-Tooth symptom subscore (P=.003), the Charcot-Marie-Tooth symptom and examination score (P=.001), the Charcot-Marie-Tooth composite score of symptoms, signs, and neurophysiology (P=.005), the MRC score (P<.0001), and NfL (P<.0001).¹

Compared with the symptomatic group, sensorimotor converters had significantly lower NIS (P=.01) and the lower limb subset (P=.01), the Charcot-Marie-Tooth symptom subscore (P=.05), and the MRC score (P=.01). Sensory converters were not significantly different from the sensorimotor converters or the asymptomatic group. Compared with sensorimotor converters, the asymptomatic group had significantly lower NfL levels at baseline (P=.002). Compared with the asymptomatic group, baseline NfL levels were 9.3-fold higher in the symptomatic group, 7.4-fold higher in the sensorimotor converters, and 2.5-fold higher in sensory converters.¹

鈥淭he mixed-effects model of NfL change over time demonstrated that, irrespective of time, NfL was higher in the symptomatic cohort and sensorimotor converters, than in the asymptomatic cohort or sensory converters (all P<.001),鈥� the authors wrote. 鈥淭he NfL was observed to rise over time most rapidly in the sensorimotor converter group, more so than the sensory converter group, although this did not reach significance.鈥�¹

Symptomatic and sensorimotor converters were discriminated from asymptomatic or sensory converter groups using a baseline NfL concentration >64.5 pg/mL, with a specificity of 78.7% and a sensitivity of 91.9% (area under the curve [AUC] = 0.87; 95% CI 0.81鈥�0.94). The same cutoff was used to discriminate asymptomatic individuals from symptomatic individuals or sensorimotor converters, with a specificity of 88.5% and a sensitivity of 92.0% (AUC = 0.95; 95% CI 0.90鈥�0.99).¹

Following treatment, the change in NfL was positively correlated with the change in TTR levels, with a greater TTR suppression correlating with reduced NfL levels. A greater reduction in NfL was also associated with greater suppression of TTR levels, where a significantly greater NfL reduction was seen in patients with >80% TTR suppression than in those with <50% TTR suppression. In individuals with >50% TTR suppression, a mixed-effects model revealed that the log(NfL) level significantly decreased over time, equating to a 36% annual decrease in NfL.¹

Conclusions

In this study, Dr. Carroll and colleagues validated the use of serum NfL in patients with ATTRv to monitor disease onset, progression, and response to treatment. Cutoff values for predicting the transition from asymptomatic to symptomatic disease were also suggested.¹

Limitations of this study include the retrospective design, a lack of uniformity of the follow-up time points, and a small sample size for certain time points, resulting in reduced analysis power.¹

鈥淚n the present study, we have validated the use of NfL in a real-life cohort to monitor disease activity, finding that NfL correlates well with disease severity and examination scores,鈥� the authors concluded in Amyloid. 鈥淲hile prospective longitudinal studies confirming our findings are required, the evidence for the utility of NfL as a useful disease biomarker is accumulating.鈥�

Published: April 23, 2024