Neurological affection and serum neurofilament light chain in wild type transthyretin amyloidosis

Abstract

In contrast to inherited transthyretin amyloidosis (A-ATTRv), neuropathy is not a classic leading symptom of wild type transthyretin amyloidosis (A-ATTRwt). However, neurological symptoms are increasingly relevant in A-ATTRwt as well. To better understand the role of neurological symptoms in A-ATTRwt, A-ATTRwt patients were prospectively characterized at Amyloidosis Center Charité Berlin (ACCB) between 2018 and 2023 using detailed neurological examination, quality of life questionnaires, and analysis of age- and BMI-adapted serum neurofilament light chain (NFL) levels. 16 out of 73 (21.9%) patients presented with a severe neuropathy which we defined by a Neuropathy Impairment Score (NIS) of 20 or more. In this group, quality of life was reduced, peripheral neuropathy was more severe, and spinal stenosis and joint replacements were frequent. Age- and BMI matched serum NFL levels were markedly elevated in patients with a NIS ≥ 20. We therefore conclude that highly abnormal values in neuropathy scores such as the NIS occur in A-ATTRwt, and have an important impact on quality of life. Both peripheral neuropathy and spinal canal stenosis are likely contributors. Serum NFL may serve as a biomarker for neurological affection in patients with A-ATTRwt. It will be important to consider neurological aspects of A-ATTRwt for diagnosis, clinical follow-up, and future treatment development.

Figure 1

Quality of life analysis of patients with severe neuropathy. Boxplots of (A) RODS and (B) Norfolk questionnaires show reduced quality of life and self-sufficiency in patients with NIS ≥ 20 compared to patients with NIS < 20. Statistics: (A) Unpaired t-test, p < 0.0001; NIS < 20: n = 37, NIS ≥ 20: n = 14. (B) Mann–Whitney-U test, p < 0.0001; NIS < 20: n = 42, NIS ≥ 20: n = 13.

Figure 2

Neurological characterization of patients of different neurological severity. (A,B) Violin plots of NIS subitem scores. (A) Affection of cranial nerves and muscle weakness in patients with NIS < 20 vs NIS ≥ 20. Scores range from 0 to 4 (B) Affection of reflexes, and proximal and distal sensation in patients with NIS < 20 vs NIS ≥ 20. Scores range from 0–2. Data for both left (L) and right (R) body sides are displayed for all items. Detailed legends for both (A) and (B) are depicted in the Score legend A and Score legend B. NIS < 20: n = 33; NIS ≥ 20: n = 13. (C,D) Comparison of nerve conduction studies (NCS) between groups of different neurological affection (by NIS). Statistics: Mann–Whitney-U test. (C) Amplitude peroneal nerve: p = 0.035; conduction velocity peroneal nerve: p = 0.124; distal motor latency peroneal nerve: p = 0.015; NIS < 20: n = 25; NIS ≥ 20: n = 8. (D) Amplitude sural nerve: p = 0.034; conduction sural nerve: p = 0.109; NIS < 20: n = 24; NIS ≥ 20: n = 8.

Figure 3

Correlation of comorbidities with NIS. (A) Spearman correlation of different comorbidities with NIS. Values of Spearman’s r range from − 1.0 to + 1.0. Diamond shapes indicate the respective correlation coefficients with the NIS. coronary heart disease = CHD; history of stroke = stroke; diabetes mellitus = DM; history of joint replacement = Joint Rx; carpal tunnel syndrome = CTS; spinal canal stenosis = SCS. (B) Boxplots depicting NIS scores of patients with or without selected comorbidities. Statistics: Mann–Whitney-U test. Spinal canal stenosis: p = 0.0002; yes: n = 18; no: n = 44. Carpal tunnel syndrome: p = 0.057; yes: n = 38; no: n = 28. History of joint replacement: p = 0.0004; yes: n = 20; no: n = 36.

Figure 4

Comparison of serum NFL levels in patients with A-ATTRwt with different severity of neuropathy. (A) Boxplots comparing serum neurofilament light chain (sNFL) age and BMI adapted levels (z-scores) as described by Benkert et al. of patients with NIS < 20 and NIS ≥ 20. Statistics: unpaired t-test; p = 0.010; NIS < 20: n = 41; NIS ≥ 20: n = 11. (B) Boxplots comparing sNFL z-scores of patients with spinal canal stenosis (SCS) and without SCS. Statistics: unpaired t-test; p = 0.526; SCS: n = 13, no SCS: n = 30.