Plasma neurofilament light chain concentration is increased and correlates with the severity of neuropathy in hereditary transthyretin amyloidosis

Kapoor, Mahima; Foiani, Martha; Heslegrave, Amanda; Zetterberg, Henrik; Lunn, Michael P.; Malaspina, Andrea; Gillmore, Julian D.; Rossor, Alexander M.; Reilly, Mary

doi:10.1111/jns.12350

Cited by 52 publications

(75 citation statements)

References 13 publications

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“…This study demonstrates that sNfL levels are increased in patients with PNP due to AL amyloidosis, and confirms previous studies showing that sNfL levels are increased and correlate with severity of PNP in patients with PNP due to ATTRv amyloidosis [18,19]. This study indicates that sNfL is a useful biomarker for PNP diagnosis and severity, not only in ATTRv, but also in AL amyloidosis.…”

Section: Discussionsupporting

confidence: 90%

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Neurofilament light chain, a biomarker for polyneuropathy in systemic amyloidosis

Louwsma

Brunger

Bijzet

et al. 2020

Amyloid

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Objective: To study serum neurofilament light chain (sNfL) in amyloid light chain (AL) amyloidosis patients with and without polyneuropathy (PNP) and to corroborate previous observations that sNfL is increased in hereditary transthyretin-related (ATTRv) amyloidosis patients with PNP. Methods: sNfL levels were assessed retrospectively in patients with AL amyloidosis with and without PNP (AL/PNPþ and AL/PNP-, respectively), patients with ATTRv amyloidosis and PNP (ATTRv/PNPþ), asymptomatic transthyretin (TTR) gene mutation carriers (TTRv carriers) and healthy controls. Healthy controls (HC) were age-and sex-matched to both AL/PNP-(HC/AL) and TTRv carriers (HC/TTRv). The single-molecule array (Simoa) assay was used to assess sNfL levels. Results: sNfL levels were increased both in 10 AL/PNPþ patients (p < .001) and in 10 AL/PNP-patients (p < .005) compared to 10 HC/AL individuals. sNfL levels were higher in AL/PNPþ patients than in AL/ PNP-patients (p < .005). sNfL levels were also increased in 15 ATTRv/PNPþ patients, compared to both 15 HC/TTRv (p < .0001) and 15 TTRv carriers (p < .0001). ATTRv/PNPþ patients with progressive PNP (PND-score > I) had the highest sNfL levels compared to patients with early PNP (PND-score I) (p ¼ .05). sNfL levels did not differ between TTRv carriers and HC/TTRv individuals. In the group comprising all healthy controls and in the group of TTRv carriers, sNfL levels correlated with age. Conclusion: sNfL levels are increased in patients with PNP in both AL and ATTRv amyloidosis and are related to severity of PNP in ATTRv amyloidosis. sNfL is a promising biomarker to detect PNP, not only in ATTRv but also in AL amyloidosis.

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Section: Discussionsupporting

confidence: 90%

“…However, the diagnostic value of sNfL as a biomarker for PNP in systemic amyloidosis has not been studied in detail. Two recent reports suggest that sNfL is increased in patients with ATTRv amyloidosis and PNP [18,19].…”

Section: Introductionmentioning

confidence: 95%

Neurofilament light chain, a biomarker for polyneuropathy in systemic amyloidosis

Louwsma

Brunger

Bijzet

et al. 2020

Amyloid

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“…NfL is a neuronal cytoplasmic protein, which is particularly highly expressed in myelinated axons. Levels of NfL in the blood proportionally increase to the degree of axonal damage in several neurological disorders, including multiple sclerosis, amyotrophic lateral sclerosis and Alzheimer's disease [29], but also in peripheral neuropathies [30][31][32]. Several patients in our control group had underlying cerebral insults that could affect the biomarker levels but still the CIN/CIM showed significantly higher levels of NfL.…”

Section: Discussionmentioning

confidence: 85%

Critical Illness Polyneuropathy and Myopathy in COVID-19 Patients: A Prospective Observational Intensive Care Unit Cross-Sectional Cohort Study

Frithiof

Rostami

Kumlien

et al. 2020

Preprint

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Background: Several reports on neurological complications associated with SARS-CoV-2 infection have been published. However, systematic description on intensive care unit acquired weakness (ICUAW) are still missing. Methods: The objective was to determine the incidence and characteristics of critical illness polyneuropathy (CIN) and myopathy (CIM) in patients with severe COVID-19. We also aimed to describe the electrophysiological features and their relation to plasma biomarkers for neuronal injury. This was a prospective observational intensive care unit cohort study. All adult patients admitted to the general intensive care unit (ICU) at Uppsala University Hospital, Uppsala, Sweden, between March 13 and June 8, 2020 were screened for inclusion. Patients with PCR confirmed COVID-19 were included. All patients were admitted to intensive care treatment due to severe COVID-19, including intravenous anaesthesia, opioid anaelgesia, neuromuscular blockade and mechanical ventilation. Associations of clinical, electrophysiological (sensory and motor conduction studies and electromyography) and biomarker data [neurofilament light chain (NfL), glial fibrillary acidic protein (GFAp) and tau] were studied between COVID-19 patients who developed CIN/CIM and those who did not. Results: 111 COVID-19 patients were included, 11 (11 males, mean age: 64 years) developed CIN/CIM whereas 100 (74 males, mean age: 61 years) did not (non-CIN/CIM). The CIN/CIM incidence was higher in COVID-19 patients compared to a general ICU-population treated during 2019 (9.9% vs 3.4%). In particular CIN was more frequent in the COVID-19 ICU cohort (50%) compared with the non-COVID-19 ICU cohort (0%, p=0.008). NfL and GFAp levels were higher in the CIN/CIM group both at the early (<9 days) and late time points (>11 days) compared with the non-CIN/CIM group (both p=0.001) and correlated with nerve amplitudes. Conclusions: CIN/CIM, in particular CIN, were more prevalent among COVID-19 patients than an ICU treated control cohort and should be considered in the differential diagnostic workup and the further rehabilitation of COVID-19 patients. COVID-19 patients who later developed ICUAW had significantly higher NfL and GFAp in the early phase of ICU care, which suggests their potential as predictive biomarkers. Trial registration: The study protocol was registered (ClinicalTrialsID:NCT04316884). Mechanisms for Organ Dysfunction in Covid-19 (UMODCOVID19) March 18, 2020.

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“…Initial results were promising when therapy was started early, and showed a decrease or cessation of disease progression, and in some cases even an improvement of clinical symptoms 4,5 . Few studies suggest the potential use of serum or CSF neurofilaments as biomarkers in different neurologic disorders, 29–31 and one study indicates that plasma neurofilament light chain concentration is increased and correlates with the clinical severity in ATTRv‐PNP 32 . However, there are still no proven biomarkers for (1) the early detection of nerve lesions that are not detectable by NCS, and (2) for the monitoring of peripheral nerve impairment under therapy.…”

Section: Discussionmentioning

confidence: 99%

Magnetization transfer ratio quantifies polyneuropathy in hereditary transthyretin amyloidosis

Kollmer

Hegenbart

Kimmich

et al. 2020

Ann Clin Transl Neurol

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Objective: To quantify peripheral nerve lesions in symptomatic and asymptomatic hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PNP) by analyzing the magnetization transfer ratio (MTR) of the sciatic nerve, and to test its potential as a novel biomarker for macromolecular changes. Methods: Twenty-five patients with symptomatic ATTRv-PNP, 30 asymptomatic carriers of the mutant transthyretin gene (mutTTR), and 20 age-/sexmatched healthy controls prospectively underwent magnetization transfer contrast imaging at 3 Tesla. Two axial three-dimensional gradient echo sequences with and without an off-resonance saturation rapid frequency pulse were conducted at the right distal thigh. Sciatic nerve regions of interest were manually drawn on 10 consecutive axial slices in the images without off-resonance saturation, and then transferred to the corresponding slices that were generated by the sequence with the off-resonance saturation pulse. Subsequently, the MTR and cross-sectional area (CSA) of the sciatic nerve were evaluated. Detailed neurologic and electrophysiologic examinations were conducted in all ATTRv-PNP patients and mutTTR-carriers. Results: Sciatic nerve MTR and CSA reliably differentiated between ATTRv-PNP, mutTTR-carriers, and controls. MTR was lower in ATTRv-PNP (26.4 AE 0.7; P < 0.0001) and in mutTTR-carriers (32.6 AE 0.8; P = 0.0005) versus controls (39.4 AE 2.1), and was also lower in ATTRv-PNP versus mutTTR-carriers (P = 0.0009). MTR correlated negatively with the NIS-LL and positively with CMAPs and SNAPs. CSA was higher in ATTRv-PNP (34.3 AE 1.7 mm 3 ) versus mutTTR-carriers (26.0 AE 1.1 mm 3 ; P = 0.0005) and versus controls (20.4 AE 1.2 mm 3 ; P < 0.0001). CSA was also higher in mutTTR-carriers versus controls. Interpretation: MTR is a novel imaging marker that can quantify macromolecular changes in ATTRv-PNP and differentiate between symptomatic ATTRv-PNP and asymptomatic mutTTRcarriers and correlates with electrophysiology.

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Plasma neurofilament light chain concentration is increased and correlates with the severity of neuropathy in hereditary transthyretin amyloidosis

Cited by 52 publications

References 13 publications

Neurofilament light chain, a biomarker for polyneuropathy in systemic amyloidosis

Neurofilament light chain, a biomarker for polyneuropathy in systemic amyloidosis

Critical Illness Polyneuropathy and Myopathy in COVID-19 Patients: A Prospective Observational Intensive Care Unit Cross-Sectional Cohort Study

Magnetization transfer ratio quantifies polyneuropathy in hereditary transthyretin amyloidosis

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