Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology

Bridel, Claire; Wieringen, Wessel N. van; Zetterberg, Henrik; Bm, Tijms; Teunissen, Charlotte E.; Jc, Alvarez-Cermeño; Andréasson, Ulf; Axelsson, Markus; Dc, Bäckström; Bartoš, Aleš; Bjerke, Maria; Blennow, Kaj; Boxer, Adam L.; Brundin, Lou; Burman, Joachim; Christensen, Tove; Fialová, L; Forsgren, Lars; Frederiksen, Jette Lautrup; Gisslén, Magnus; Gray, Elizabeth; Gunnarsson, Martin; Hall, Sara; Hansson, Oskar; Herbert, Megan K.; Jakobsson, Joel; Jessen-Krut, J; Janelidze, Shorena; Johannsson, Gudmundur; Jonsson, Michael; Kappos, Ludwig; Khademi, Mohsen; Khalil, Michael; Kühle, Jens; Landén, Mikael; Leinonen,; Logroscino, Giancarlo; Lu, Chien-Hsing; Lycke, Jan; Nk, Magdalinou; Malaspina, Andrea; Mattsson, Niklas; Lh, Meeter; Mehta,; Modvig, Signe; Olsson, Tomas; Paterson, Ross W.; Pérez-Santiago, Josué; Piehl, Fredrik; Yal, Pijnenburg; Ot, Pyykkö; Ragnarsson, Oskar; Jc, Rojas; Christensen, Jeppe Romme; Sandberg, Linda; Cs, Scherling; Schott, Jonathan M.; Sellebjerg, Finn; Simone, IL; Skillbäck, Tobias; Stilund, Morten; Sundström, Peter; Svenningsson, Anders; Tortelli, Rosanna; Tortorella, Carla; Trentini, Alessandro; Troiano, Maria; Turner, Martin R; Jc, van Swieten; Vågberg, Mattias; Verbeek, MM; Lm, Villar; Visser, Pieter Jelle; Wallin, Anders; Weiss, Andreas; Wikkelsø, Carsten; Wild, Edward J.

doi:10.1001/jamaneurol.2019.1534

Cited by 563 publications

(483 citation statements)

References 140 publications

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“…Our findings provide insights into why NEFL is a promising biomarker for AD dementia and its progression as shown by studies of CSF and plasma NEFL in AD 49,50,54,55 .…”

Section: Discussionmentioning

confidence: 68%

“…Among the 23 proteins associated with both cognitive diagnosis and cerebral atherosclerosis independently of the other 8 measured pathologies, NEFL and NEFM were noteworthy since prior work has shown that their CSF levels associated with AD (Table 1B) [48][49][50] . In light of these findings, we examined whether NEFL and NEFM were associated with cerebral atherosclerosis specifically or with other measured pathologies as well.…”

Section: Nefl and Nefm Proteins Are Associated With Cerebral Atheroscmentioning

confidence: 98%

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Cerebral atherosclerosis contributes to Alzheimer’s dementia independently of its hallmark amyloid and tau pathologies

Wingo

Fan

Duong

et al. 2019

Preprint

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Cerebral atherosclerosis is a leading cause of stroke and an important contributor to dementia. However, little is known about its molecular effects on the human brain and how these alterations may contribute to dementia. Here, we investigated these questions using large-scale quantification of over 8300 proteins from 438 post-mortem brains from a discovery and replication cohort. A proteome-wide association study and protein network analysis of cerebral atherosclerosis found 114 proteins and 5 protein co-expression modules associated with cerebral atherosclerosis. Enrichment analysis of these proteins and modules revealed that cerebral atherosclerosis was associated with reductions in synaptic signaling and RNA splicing and increases in oligodendrocyte development and myelination.A subset of these proteins (n=23) and protein modules (n=2) were also associated with Alzheimer's disease (AD) dementia, implicating a shared mechanism with AD through decreased synaptic signaling and regulation and increased myelination. Notably, neurofilament light (NEFL) and medium (NEFM) chain proteins were among these 23 proteins, and our data suggest they contribute to AD dementia through cerebral atherosclerosis. Together, our findings offer insights into effects of cerebral atherosclerosis on the human brain proteome, and how cerebral atherosclerosis contributes to dementia risk.

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“…Our findings provide insights into why NEFL is a promising biomarker for AD dementia and its progression as shown by studies of CSF and plasma NEFL in AD 49,50,54,55 .…”

Section: Discussionmentioning

confidence: 68%

Section: Nefl and Nefm Proteins Are Associated With Cerebral Atheroscmentioning

confidence: 98%

Cerebral atherosclerosis contributes to Alzheimer’s dementia independently of its hallmark amyloid and tau pathologies

Wingo

Fan

Duong

et al. 2019

Preprint

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“…The 68 kDa neurofilament light chain (NfL) is essential for the assembly of the complex as it forms its backbone and is released into extracellular fluids in response to axonal damage. 6,7 Several studies have shown elevated levels of NfL in the CSF of patients suffering from neurodegenerative conditions. [7][8][9] Further, CSF NfL levels seem to reflect progression of various neurological conditions, including multiple sclerosis and neurodegenerative dementia disorders.…”

Section: Introductionmentioning

confidence: 99%

“…6,7 Several studies have shown elevated levels of NfL in the CSF of patients suffering from neurodegenerative conditions. [7][8][9] Further, CSF NfL levels seem to reflect progression of various neurological conditions, including multiple sclerosis and neurodegenerative dementia disorders. 10,11 Ultrasensitive methods have enabled the quantification of NfL in serum.…”

Section: Introductionmentioning

confidence: 99%

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Validation of Serum Neurofilament Light Chain as a Biomarker of Parkinson’s Disease Progression

Mollenhauer

Dakna

Liu

et al. 2019

Preprint

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Background: Alterations in neurofilament light chain (NfL), reflecting axonal damage, have been proposed as a biomarker for neurological disorders including Parkinson's disease (PD). Methods:We measured NfL concentrations by immunoassay in (1) a set of longitudinal CSF samples from 82 PD, 14 other neurodegenerative disorders (OND), and 53 healthy controls (HC);(2) A cross-sectional cohort with paired CSF and serum samples from subjects with 151 PD, 344 OND, and 20 HC, and (3a) a large longitudinal validation cohort with serum samples from 375 PD, 178 HC, and 57 prodromal Lewy Body disorder with hyposmia or isolated REM sleep behaviour disorder (iRBD), (3b) 216 symptomatic and 298 asymptomatic LRRK2, GBA, and SNCA mutation carriers in the Parkinson's Progression Markers Initiative (PPMI). Mean differences in serum NfL levels between diagnostic groups, and correlation with motor signs, cognitive measures and dopamine transporter imaging, were assessed. Linear mixed effects models were used to assess longitudinal changes in log10 (NfL) in relation to demographic, clinical, and imaging variables. Findings:In the longitudinal cohort (1) NfL in CSF increased over time and was significantly positively correlated with MDS-UPDRS III motor and total scores in the PD group (p=0·0231 and 0·0081). In the cross-sectional cohort (2) the paired CSF and serum NfL samples were highly correlated (Spearman's rank ߩ ො ൌ 0 7 3 ; p<10^-6). In the large validation cohort (3a) mean baseline serum NfL was higher in PD (13 ±7·2pg/ml), hyposmics (15±15·1pg/ml), and iRBD (17±8pg/ml) compared with HC (12±6·7pg/ml) but was highest in the seven OND cases (18±7pg/ml). In the genetic cohort (3b), serum NfL levels were lower in asymptomatic than in symptomatic mutation carriers. There was a significant (age-adjusted) longitudinal increase in serum NfL in PD compared with HC. Serum NfL values were significantly positively associated with longitudinal MDS-UPDRS motor and total scores, as well as age. Interpretation: We identified NfL as the first blood-based PD progression biomarker. NfL levels in serum samples are increased in PD compared to HC, increase significantly over time in PD, and correlate with a clinical measure of disease severity. Although the specificity of NfL in PD is low and additional, more specific biomarkers are needed, serum NfL is the first blood-based biomarker candidate that could support disease stratification (PD vs. OND), track clinical progression, and might be used to assess responsiveness to neuroprotective treatments. M o l l e n h a u e r 5Neurofilaments are highly phosphorylated neuronal cytoskeleton components composed of three subunits of differing molecular weight maintaining neuronal structure and determining axonal calibre. The 68 kDa neurofilament light chain (NfL) is essential for the assembly of the complex as it forms its backbone and is released into extracellular fluids in response to axonal damage. 6,7 Several studies have shown elevated levels of NfL in the CSF of patients suffering from neurodegenerativ...

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Types and Concentrations of Blood-Based Biomarkers in Adults With Peripheral Neuropathies

et al. 2022

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ImportancePeripheral neuropathies are common conditions and can result in numbness, paresthesia, motor deficits, and pain. There is increasing evidence for the use of biomarkers as clinical indicators of the presence, severity, and prognosis of nerve lesions; however, biomarker identification has largely been focused on disorders of the central nervous system, and less is known about their role in the peripheral nervous system.ObjectiveTo assess blood-based biomarker concentrations associated with nerve involvement in patients with peripheral neuropathy compared with control participants.Data SourcesOvid, MEDLINE, Embase, and CINAHL were searched from inception to September 23, 2021.Study SelectionObservational studies reporting on blood biomarkers in patients diagnosed with peripheral neuropathy were included. This review was preregistered on PROSPERO and followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data were abstracted by 1 investigator and independently reviewed by a second.Data Extraction and SynthesisData were meta-analyzed when at least 2 studies reported the same biomarker with comparable methodology. Fixed-effects models were used when only 2 studies were included; random-effects models were used when more than 2 studies were included.Main Outcomes and MeasuresThe outcome of interest was concentration of biomarkers.ResultsThis review included 36 studies reporting on 4414 participants, including 2113 control participants and 2301 patients with peripheral neuropathy with 13 distinct peripheral neuropathy diagnoses. Diabetic neuropathy was the most common neuropathy diagnosis (13 studies), followed by Charcot-Marie-Tooth disease (6 studies) and Guillain-Barre syndrome (6 studies). Overall, 16 different blood-based biomarkers associated with nerve involvement were evaluated. The most used were neurofilament light chain, S100B, brain-derived neurotrophic factor, and neuron-specific enolase. Patients with peripheral neuropathy demonstrated significantly higher levels of neurofilament light chain compared with controls (standardized mean difference [SMD], 0.93 [95% CI, 0.82 to 1.05]; P &lt; .001). There were no significant differences in levels of S100B (SMD, 1.10 [95% CI, −3.08 to 5.28]; P = .38), brain-derived neurotrophic factor (SMD, −0.52 [95% CI, −2.23 to 1.19]; P = .40), or neuron-specific enolase (SMD, −0.00 [95% CI, −1.99 to 1.98]; P = .10) in patients with peripheral neuropathy compared with control participants.Conclusions and RelevanceThe findings of this systematic review and meta-analysis support the use of neurofilament light chain as a blood-based measure associated with the presence of neuronal injury in patients with peripheral neuropathy.

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Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology

Cited by 563 publications

References 140 publications

Cerebral atherosclerosis contributes to Alzheimer’s dementia independently of its hallmark amyloid and tau pathologies

Cerebral atherosclerosis contributes to Alzheimer’s dementia independently of its hallmark amyloid and tau pathologies

Validation of Serum Neurofilament Light Chain as a Biomarker of Parkinson’s Disease Progression

Types and Concentrations of Blood-Based Biomarkers in Adults With Peripheral Neuropathies

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