Serum neurofilament light chain as a reliable biomarker of hereditary transthyretin‐related amyloidosis—A Swiss reference center experience

Abstract

Hereditary transthyretin-related (hATTR) amyloidosis is a rare disease, causing a disabling and life-threatening axonal length-dependent polyneuropathy. Monitoring of disease progression and treatment response is difficult. We aimed to determine if serum neurofilament light chain (sNfL) is a reliable and early biomarker of peripheral neuropathy in hATTR amyloidosis. We prospectively included 20 hATTR patients, 14 symptomatic and 6 asymptomatic. Patients were assessed at baseline and 1 year, including a full clinical examination with disease severity and functional scores, electrochemical skin conductance measurement with Sudoscan and nerve conduction studies, and sNfL level. hATTR patient sNfL were also compared with sNfL of 4532 healthy controls of a reference database by calculating age and BMI-adjusted Z scores. At baseline, median sNfL concentration was 3.6-fold higher in symptomatic than asymptomatic hATTR patients (P = .003), and this difference was also found in our under 60-years-old patients (P = .003). There was no significant difference of sNfL concentration between asymptomatic patients and healthy controls (Z-score of À0.29), but a significant difference between symptomatic patients and healthy controls (Z-score of 2.52). We found a significant correlation between sNfL levels and most clinical and electrophysiological disease severity scores, the strongest correlation being with the NIS score. sNfL seems to be a reliable biomarker of peripheral neuropathy severity in hATTR amyloidosis and can distinguish between asymptomatic and symptomatic patients. sNfL could also become a reliable biomarker to establish disease onset and treatment response.

Serum neurofilament light chain: a promising early diagnostic biomarker for hereditary transthyretin amyloidosis?

“…Our findings confirm that sNfL levels are increased in patients with symptomatic ATTRv amyloidosis compared to both presymptomatic carriers and HCs (around 5‐ and 4‐fold higher, respectively). Notwithstanding the different methods used (Ella in our study), our results are in line with previous studies showing plasma or sNfL levels 3–10 times higher in patients compared to still presymptomatic carriers and controls [9–14]. Interestingly, there was no significant difference when stratifying ATTRv patients based on the phenotype.…”

“…However, it lacks specificity, as elevated levels have been reported in several diseases involving either the central or peripheral nervous system [17]. So far, the most robust data refer to patients with multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, frontotemporal dementia and parkinsonism [21–23], but growing evidence supports its potential role also in disorders involving the peripheral nervous system, including ATTRv amyloidosis [9–14].…”

“…Previous studies aimed at defining an NfL threshold able to discriminate presymptomatic carriers from symptomatic ATTRv patients reported extremely variable values [10, 12, 14]. In fact, the specific cut‐off may vary depending on the used immunoassay (SiMoA vs. Ella) and the specific sample (plasma vs. serum).…”

“…In the last few years, several reports have supported the role of neurofilament light chain (NfL) as a possible biomarker for subclinical disease in ATTRv amyloidosis [9][10][11][12][13][14]. Neurofilaments are major proteins of the neuronal cytoskeleton and are composed of three subunits: heavy, medium and light chains [15].…”

“…Since ATTRv amyloidosis is characterized by a progressive mainly axonal polyneuropathy, NfL may represent a reliable biomarker of disease progression and severity. Furthermore, preliminary data suggest that NfL may also represent a sensitive marker of disease onset, helping to discriminate still‐asymptomatic TTR mutation carriers from early symptomatic patients [9–11, 14]. Raised levels of NfL may indeed occur even before symptom onset and evidence of detectable abnormalities on clinical examination and nerve conduction studies.…”