Longitudinal analysis of serum neurofilament light chain levels as marker for neuronal damage in hereditary transthyretin amyloidosis

Figures & data

Table 1. Characteristics of TTRv carriers and ATTRv amyloidosis patients.

Persistently asymptomatic TTRv carriers (N = 12)
	t = 0	t = 1	p-value
Gender (m/f)	5/7
Genotype (TTRV30M/other*)	9/3
Age (years)	49 ± 13	51 ± 12
Follow-up (months)	0	26 ± 19
TTR-stabiliser (none/diflunisal/tafamidis)	12/0/0	8/4/0
TTR-silencer (patisiran)	0	0
PND score 0	12	12
NCS abnormal	0	0
Cardiac involvement	0	0
NT-proBNP (ng/L)	58 (16−86)	39 (13–116)	0.78
Troponin T (ng/L)	4 (2–7)	5 (3–6)	0.48
Creatinine (µmol/L)	76 (68−78)	77 (69–87)	0.06
sNfL (pg/mL)	8.2 (5.7−10.4)	8.2 (7.0−14.1)	0.09
Persistently asymptomatic ATTRv patients (N = 8)
	t = 0	t = 1
Gender (m/f)	4/4
Genotype (TTRV30M/other*)	6/2
Age (years)	39 ± 14	42 ± 14
Follow-up (months)	0	27 ± 10
TTR-stabiliser (none/diflunisal/tafamidis)	6/2/0	0/8/0
TTR-silencer (patisiran)	8/0	8/0
PND score 0	8	8
NCS abnormal	0	0
Cardiac involvement	0	0
NT-proBNP (ng/L)	32 (18–109)	45 (11−74)	0.47
Troponin T (ng/L)	3 (2–6)	5 (2–7)	0.06
Creatinine (µmol/L)	75 (63–87)	78 (66–97)	0.13
sNfL (pg/mL)	7.1 (5.5−11.2)	11.1 (7.5−17.5)	0.01
TTRv carriers who developed PNP (N = 7)
	t = 0*	t = 1**
Gender (m/f)	1/6
Genotype (TTRV30M/other*)	2/5
Age (years)	37 ± 10	47 ± 12
Follow-up (months)	0	126 ± 50
TTR-stabiliser (none/diflunisal/tafamidis)	4/3/0	0/7/0
TTR-silencer (patisiran)	0	0
PND score
0	7	0
≥ I	0	7
NCS (normal/abnormal)	7/0	1***/6
Cardiac involvement	0	1
NT-proBNP (ng/L)	42 (24–82)	97 (69–173)	0.02
Troponin T (ng/L)	2 (2–5)	7 (5–8)	0.14
Creatinine (µmol/L)	78 (59–82) (N = 6)	67 (55−72)	0.06
sNfL (pg/mL)	8.4 (7.6−9.4)	49.8 (45.4−60.5)	0.02
ATTRv amyloidosis patients with PNP on TTR-stabiliser (N = 20)
	t = 0	t = 1
Gender (m/f)	15/5
Genotype (TTRV30M/other*)	9/11
Age (years)	60 ± 15	62 ± 15
Follow-up (months)	0	25 ± 12
TTR-stabiliser (none/diflunisal/tafamidis)	12/3/5	0/3/17
TTR-silencer (patisiran)	0	0
PND score
I	14	12
> I	6	8
NCS abnormal	19	20
Cardiac involvement	13	14
NT-proBNP (ng/L)	180 (75–2169)	364 (80–3110)	<0.001
Troponin T (ng/L)	21 (8–36)	20 (9–54)	0.02
Creatinine (µmol/L)	71 (79–102)	70 (74–89)	0.57
sNfL (pg/mL)	43.2 (18.1−68.7)	41.6 (17.9−70.1)	0.39
ATTRv amyloidosis patients with PNP on TTR-silencer (N = 18)
	t = 0	t = 1
Gender (m/f)	14/4
Genotype (TTRV30M/other*)	14/4
Age (years)	58 ± 15	60 ± 15
Follow-up (months)	0	14 ± 3.4
TTR-stabiliser (none/diflunisal/tafamidis)	0/4/4	0/5/5
TTR-silencer (patisiran)	0	18
PND score
I	8	8
> I	10	10
NCS abnormal	18	18
Cardiac involvement	13	13
NT-proBNP (ng/L)	284 (68−616)	290 (90–907)	0.32
Troponin T (ng/L)	23 (10–36)	19 (8–35)	0.51
Creatinine (µmol/L)	72 (63–88)	75 (61–86)	0.57
sNfL (pg/mL)	61.2 (28.6–120)	37.7 (24.6−45.5)	<0.001

Data are expressed as mean ± standard deviation when normally distributed and median (interquartile range) when non-normally distributed. TTR-stabiliser: treatment with a transthyretin stabiliser; PNP: polyneuropathy; PND: polyneuropathy disability; NCS: nerve conduction studies; NT-proBNP: N-terminal prohormone of brain natriuretic peptide; sNfL: serum neurofilament light chain; t: timepoint at which levels of sNfL were measured; t = 0: first timepoint at which levels of sNfL were measured; t = 1: second timepoint at which levels of sNfL were measured.

*See Supporting Information Table S1 for a specification of genotypes.

**In variant carriers who developed polyneuropathy, t = 0 refers to the first timepoint of evaluation at the Expertise Centre, t = 1 refers to the timepoint at which the first PND score I.

***Abnormal quantitative sensory testing results.

Figure 1. sNfL levels in the asymptomatic group. (A) sNfL levels in persistently asymptomatic TTRv carriers (amyloid negative) and in persistently asymptomatic ATTRv patients (amyloid positive) over approximately 2 years. (B) Change of sNfL per month (delta sNfL) in persistently asymptomatic TTRv carriers and in persistently asymptomatic ATTRv patients. sNfL: serum neurofilament light chain; t = 0: first timepoint at which levels of sNfL were measured; t = 1: second timepoint at which levels of sNfL were measured.

Figure 2. sNfL in TTRv carriers who developed polyneuropathy. sNfL levels at t = 0 (first sample available, asymptomatic stage), t = last PND score 0 (sample at the last asymptomatic timepoint), t = first PND score I (sample at the first symptomatic timepoint where the PND score is at least I). sNfL: serum neurofilament light chain; PND: polyneuropathy disability.

Figure 3. sNfL levels in ATTRv patients with polyneuropathy. (A) sNfL levels in ATTRv patients with polyneuropathy treated with a TTR-stabiliser over approximately 2 years and sNfL levels in ATTRv patients with polyneuropathy treated with a TTR-silencer over approximately 1 year. (B) Change of sNfL per month (delta sNfL) in ATTRv patients with polyneuropathy treated with a TTR-stabiliser or a TTR-silencer. Closed dots represent patients on a TTR-stabiliser or TTR-silencer only and open dots represent patients on combined treatment with a TTR-stabiliser and TTR-silencer. sNfL: serum neurofilament light chain; t = 0: first timepoint at which levels of sNfL were measured; t = 1: second timepoint at which levels of sNfL were measured.

Figure 4. Comparison of sNfL between the asymptomatic group and TTRv carriers who developed polyneuropathy. (A) sNfL levels in the merged group of persistently asymptomatic TTRv carriers and ATTRv patients at t = 1 compared to the TTRv carriers who developed polyneuropathy at t = last PND score 0. (B) Change in sNfL per month (delta sNfL) in the merged group of persistently asymptomatic TTRv carriers and ATTRv patients between t = 0 and t = 1 compared to the delta sNfL in the TTRv carriers who developed polyneuropathy between t = last PND score 0 and t = first PND score I. sNfL: serum neurofilament light chain; PND: Polyneuropathy Disability; PNP: polyneuropathy; t = 1: second timepoint at which levels of sNfL were measured.

Data availability statement

The datasets generated during and/or analysed during this study are available from the corresponding author on reasonable request.