Neurofilament light chain as a biological marker for multiple sclerosis: a meta-analysis study

Figures & data

Figure 1 Flowchart depicting literature search and study selection.

Notes: Flow diagram of systematic search in the three databases. After removal of duplicates, reviews, and quality control, 13 articles were suitable for analysis.
Abbreviations: NFH, neurofilament heavy; NFL, neurofilament light.

Table 1 Characteristics of studies involved in the meta-analysis

Author, year	Country	Gender (% male)		Mean age (years)		Disease duration (year)	Sample origin	N		MS (NFL ng/L)		HC (NFL ng/L)
		MS	HC	MS	HC			MS	HC	Mean	SD	Mean	SD
Novakova et al, 2017^Citation96	Sweden	29.9	59.5	37	28	NA	CSF	204	42	730	82,807	205	903.7
Haghighi et al, 2004^Citation98	Sweden	NA	NA	44	33	NA	CSF	47	50	258.7	186.7	128.3	15.8
Norgren et al, 2003^Citation99	Sweden	NA	NA	NA	NA	NA	CSF	5	11	2,500	3,354	31	76.3
Rosengren et al, 1996^Citation100	Sweden	NA	NA	35.6	53	8	CSF	5	11	463	402	128	6
Novakova et al, 2017^Citation101	Sweden	71.4	64.1	37	34	6.6	CSF	7	39	1,900	1,722	364	302.3
Novakova et al, 2017^Citation102	Sweden	37.2	64.1	39.7	33.6	NA	CSF	43	39	1,183	2,135	364	254
Håkansson et al, 2017^Citation103	Sweden	22	23	31	32	0.98	CSF	41	22	895	1,304	212	102.2
Novakova et al, 2015^Citation104	Sweden	35.5	68.8	36	41	8.4	CSF	31	16	2,391	5,274	308	95
Zhang et al, 2007^Citation105	China	36.5	43.5	39	29	8	CSF	63	46	26	33	10	7
Malmeström et al, 2003^Citation106	Sweden	47.8	70	32.4	35.4	7.9	CSF	23	50	1,727	1,711	125	152.5
Novakova et al, 2017^Citation96	Sweden	29.9	59.5	37	28	NA	Serum	204	42	16.9	1,095	10.5	44.4
Disanto et al, 2017^Citation97	Switzerland	35.2	31.9	37.9	44.3	NA	Serum	142	254	35.9	29.3	22.9	10.8
Disanto et al, 2017^Citation97	Switzerland	34.1	31.9	42.2	44.3	7.4	Serum	719	254	29.4	18.6	22.9	10.8
Kuhle et al, 2016^Citation107	Switzerland	35.5	44	32	31	3.6	Serum	31	18	9	17.4	1.3	3.9
Disanto et al, 2016^Citation108	Switzerland	33	37	30.6	35	0.31	Serum	100	92	24.1	28.4	7.9	8.6

Abbreviations: CSF, cerebrospinal fluid; HC, healthy control; MS, multiple sclerosis; N, number; NA, not available; NFL, neurofilament light chain.

Figure 2 Meta-analysis of neurofilament light chain levels in CSF between MS patients and healthy controls.

Notes: The random-effect model was used. Unit of CSF neurofilament light chain level was ng/L. There was a highly significant difference between the two groups (P<0.00001).
Abbreviations: CSF, cerebrospinal fluid; IV, inverse variance; MS, multiple sclerosis.

Figure 3 Meta-analysis of neurofilament light chain levels in blood between MS patients and healthy controls.

Notes: The random-effect model was applied. Unit of blood neurofilament light chain level was ng/L. There was a highly significant difference between the two groups (P<0.0001).
Abbreviations: IV, inverse variance; MS, multiple sclerosis.

Figure 4 Subgroup analysis stratified by age for MS in CSF.

Notes: The random-effect model was used. Unit of CSF neurofilament light chain level was ng/L.
Abbreviations: CSF, cerebrospinal fluid; IV, inverse variance; MS, multiple sclerosis.

Figure 5 Subgroup analysis stratified by neurofilament light chain concentration for MS in CSF.

Notes: The random-effect model was used. Unit of CSF neurofilament light chain level was ng/L.
Abbreviations: CSF, cerebrospinal fluid; IV, inverse variance; MS, multiple sclerosis.

Figure 6 Subgroup analysis stratified by publication year for MS in CSF.

Notes: The random-effect model was used. Unit of CSF neurofilament light chain level was ng/L.
Abbreviations: CSF, cerebrospinal fluid; IV, inverse variance; MS, multiple sclerosis.

Figure 7 Subgroup analysis stratified by sample size for MS in blood.

Notes: The random-effect model was used. Unit of blood neurofilament light chain level was ng/L.
Abbreviations: IV, inverse variance; MS, multiple sclerosis.

Figure 8 Meta-regression of CSF NFL chain in MS patients relative to healthy controls.

Notes: Separate meta-regressions of age (A), sample size (B), gender (C), and disease duration (D) between MS patients and HCs on SMDs comparing the CSF NFL chain levels in MS patients with those in HC.
Abbreviations: CSF, cerebrospinal fluid; HC, healthy control; MS, multiple sclerosis; NFL, neurofilament light; SMD, standard mean difference.

Figure 9 The publication bias of included studies when comparing the CSF (A) and blood (B) neurofilament light chain levels in MS patients with healthy controls.

Abbreviations: CSF, cerebrospinal fluid; MS, multiple sclerosis; SE, standard error; SMDs, standard mean differences.

Table S1 Quality scores of included studies

Study	Selection	Comparability	Exposure	Total
Novakova et al, 2017^Citation1	3	1	3	7
Disanto et al, 2017^Citation2	3	2	3	8
Haghighi et al, 2004^Citation3	3	1	3	7
Norgren et al, 2003^Citation4	3	0	3	6
Rosengren et al, 1996^Citation5	3	1	3	7
Novakova et al, 2017^Citation6	3	1	3	7
Novakova et al, 2017^Citation7	3	1	3	7
Håkansson et al, 2017^Citation8	3	2	3	8
Novakova et al, 2015^Citation9	3	1	3	7
Zhang et al, 2007^Citation10	3	2	3	8
Malmeström et al, 2003^Citation11	3	1	3	7
Kuhle et al, 2016^Citation12	3	1	3	7
Disanto et al, 2016^Citation13	3	2	3	8

Table S2 Results of sensitivity analysis

Including condition	Weighted standard mean difference			Heterogeneity
	Effect size	95% CI	P-value	I^2 (%)	P-value
Sensitivity analysis in CSF
Novakova et al, 2017^Citation1	0.98	[0.64, 1.32]	<0.00001	65	0.003
Haghighi et al, 2004^Citation3	0.88	[0.45, 1.30]	<0.0001	80	<0.00001
Norgren et al, 2003^Citation4	0.86	[0.46, 1.25]	<0.0001	81	<0.00001
Rosengren et al, 1996^Citation5	0.85	[0.46, 1.24]	<0.0001	80	<0.0001
Novakova et al, 2017^Citation6	0.76	[0.41, 1.12]	<0.0001	75	<0.0001
Novakova et al, 2017^Citation7	0.94	[0.51, 1.37]	<0.0001	81	<0.00001
Håkansson et al, 2017^Citation8	0.92	[0.50, 1.35]	<0.0001	81	<0.00001
Novakova et al, 2015^Citation9	0.94	[0.52, 1.35]	<0.0001	81	<0.00001
Zhang et al, 2007^Citation10	0.93	[0.49, 1.38]	<0.0001	81	<0.0001
Malmeström et al, 2003^Citation11	0.77	[0.41, 1.12]	<0.0001	73	0.0002
Sensitivity analysis in blood
Novakova et al, 2017^Citation1	0.57	[0.37, 0.78]	<0.00001	61	0.05
Disanto et al, 2017^Citation2	0.42	[0.13, 0.70]	0.004	73	0.01
Disanto et al, 2017^Citation2	0.5	[0.17, 0.84]	0.003	77	0.005
Kuhle et al, 2016^Citation12	0.47	[0.20, 0.73]	0.0005	80	0.002
Disanto et al, 2016^Citation13	0.4	[0.15, 0.66]	0.002	73	0.01

Abbreviation: CSF, cerebrospinal fluid.

Table S3 Results of subgroup analysis

Including condition	Number of groups	Weighted standard mean difference			Heterogeneity
		Effect size	95% CI	P-value	I^2 (%)	P-value
Subgroup analysis in CSF
Age
Age-matched	7	0.89	[0.35, 1.43]	0.001	84	,0.00001
Not age-matched	3	0.85	[0.50, 1.20]	<0.00001	27	0.25
NFL concentration
Cutoff <1,000 ng/L	5	0.64	[0.20, 1.07]	0.004	75	0.003
Cutoff >1,000 ng/L	5	1.16	[0.51, 1.82]	0.0005	79	0.0009
Publication year
Before 2010	5	1.11	[0.68, 1.54]	<0.00001	58	0.05
After 2010	5	0.65	[0.13, 1.17]	0.01	80	0.0005
Subgroup analysis in blood
Sample size
Less than 200	3	0.68	[0.52, 0.85]	<0.00001	0	0.78
More than 200	2	0.23	[−0.12, 0.59]	0.19	74	0.05

Note: Sub-group analysis stratified by sample size for multiple sclerosis in blood (less than 200 and more than 200).

Abbreviation: CSF, cerebrospinal fluid.

NovakovaLZetterbergHSundströmPMonitoring disease activity in multiple sclerosis using serum neurofilament light proteinNeurology201789222230223729079686

 PubMed Web of Science ®Google Scholar

HaghighiSAndersenOOdénARosengrenLCerebrospinal fluid markers in MS patients and their healthy siblingsActa Neurol Scand20041092979914705970

 PubMed Web of Science ®Google Scholar

NorgrenNRosengrenLStigbrandTElevated neurofilament levels in neurological diseasesBrain Res20039871253114499942

 PubMed Web of Science ®Google Scholar

RosengrenLEKarlssonJEKarlssonJOPerssonLIWikkelsøCPatients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSFJ Neurochem1996675201320188863508

 PubMed Web of Science ®Google Scholar

NovakovaLAxelssonMKhademiMCerebrospinal fluid biomarkers as a measure of disease activity and treatment efficacy in relapsing-remitting multiple sclerosisJ Neurochem2017141229630427787906

 PubMed Web of Science ®Google Scholar

NovakovaLAxelssonMKhademiMCerebrospinal fluid biomarkers of inflammation and degeneration as measures of fingolimod efficacy in multiple sclerosisMult Scler J20172316271

 PubMed Web of Science ®Google Scholar

HåkanssonITisellACasselPNeurofilament light chain in cerebrospinal fluid and prediction of disease activity in clinically isolated syndrome and relapsing-remitting multiple sclerosisEur J Neurol201724570371228261960

 PubMed Web of Science ®Google Scholar

NovakovaLAxelssonMMalmeströmCReduced cerebrospinal fluid concentrations of oxysterols in response to natalizumab treatment of relapsing remitting multiple sclerosisJ Neurol Sci20153581–220120626342940

 PubMed Web of Science ®Google Scholar

ZhangYLiXQiaoJNeurofilament protein light in multiple sclerosisZhonghua Yi Xue Za Zhi200787392745274918167263

 PubMedGoogle Scholar

MalmeströmCHaghighiSRosengrenLAndersenOLyckeJNeurofilament light protein and glial fibrillary acidic protein as biological markers in MSNeurology200361121720172514694036

 PubMed Web of Science ®Google Scholar

DisantoGBarroCBenkertPSerum neurofilament light: A biomarker of neuronal damage in multiple sclerosisAnn Neurol201781685787028512753

 PubMed Web of Science ®Google Scholar

KuhleJBarroCDisantoGSerum neurofilament light chain in early relapsing remitting MS is increased and correlates with CSF levels and with MRI measures of disease severityMult Scler201622121550155926754800

 PubMed Web of Science ®Google Scholar

DisantoGAdiutoriRDobsonRSerum neurofilament light chain levels are increased in patients with a clinically isolated syndromeJ Neurol Neurosurg Psychiatry201687212612925716934

 PubMed Web of Science ®Google Scholar

NovakovaLZetterbergHSundströmPMonitoring disease activity in multiple sclerosis using serum neurofilament light proteinNeurology201789222230223729079686

 PubMed Web of Science ®Google Scholar

DisantoGBarroCBenkertPSerum neurofilament light: A biomarker of neuronal damage in multiple sclerosisAnn Neurol201781685787028512753

 PubMed Web of Science ®Google Scholar

HaghighiSAndersenOOdénARosengrenLCerebrospinal fluid markers in MS patients and their healthy siblingsActa Neurol Scand20041092979914705970

 PubMed Web of Science ®Google Scholar

NorgrenNRosengrenLStigbrandTElevated neurofilament levels in neurological diseasesBrain Res20039871253114499942

 PubMed Web of Science ®Google Scholar

RosengrenLEKarlssonJEKarlssonJOPerssonLIWikkelsøCPatients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSFJ Neurochem1996675201320188863508

 PubMed Web of Science ®Google Scholar

NovakovaLAxelssonMKhademiMCerebrospinal fluid biomarkers as a measure of disease activity and treatment efficacy in relapsing-remitting multiple sclerosisJ Neurochem2017141229630427787906

 PubMed Web of Science ®Google Scholar

NovakovaLAxelssonMKhademiMCerebrospinal fluid bio-markers of inflammation and degeneration as measures of fingolimod efficacy in multiple sclerosisMult Scler J20172316271

 PubMed Web of Science ®Google Scholar

HåkanssonITisellACasselPNeurofilament light chain in cerebrospinal fluid and prediction of disease activity in clinically isolated syndrome and relapsing-remitting multiple sclerosisEur J Neurol201724570371228261960

 PubMed Web of Science ®Google Scholar

NovakovaLAxelssonMMalmeströmCReduced cerebrospinal fluid concentrations of oxysterols in response to natalizumab treatment of relapsing remitting multiple sclerosisJ Neurol Sci20153581–220120626342940

 PubMed Web of Science ®Google Scholar

ZhangYLiXQiaoJNeurofilament protein light in multiple sclerosisZhonghua Yi Xue Za Zhi200787392745274918167263

 PubMedGoogle Scholar

MalmeströmCHaghighiSRosengrenLAndersenOLyckeJNeurofilament light protein and glial fibrillary acidic protein as biological markers in MSNeurology200361121720172514694036

 PubMed Web of Science ®Google Scholar

KuhleJBarroCDisantoGSerum neurofilament light chain in early relapsing remitting MS is increased and correlates with CSF levels and with MRI measures of disease severityMult Scler201622121550155926754800

 PubMed Web of Science ®Google Scholar

DisantoGAdiutoriRDobsonRSerum neurofilament light chain levels are increased in patients with a clinically isolated syndromeJ Neurol Neurosurg Psychiatry201687212612925716934

 PubMed Web of Science ®Google Scholar