Prognostic value of serum neurofilaments in patients with clinically isolated syndromes

Costa, Gloria Dalla; Martinelli, Vittorio; Sangalli, Francesca; Moiola, Lucia; Colombo, Bruno; Radaelli, Marta; Leocani, Letizia; Furlan, Roberto; Comı, Gıancarlo

doi:10.1212/wnl.0000000000006902

Cited by 63 publications

(44 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our findings of higher baseline sNfL levels, higher concurrent inflammatory activity, and future WBV atrophy are in line with several previous reports . Associations between baseline sNfL levels, T 2 ‐LV, and Gd–enhancing lesions have been demonstrated as early as at the first demyelinating event, and are able to significantly predict conversion to clinically definite MS .…”

Section: Discussionsupporting

confidence: 92%

Serum neurofilament light chain levels associations with gray matter pathology: a 5‐year longitudinal study

Jakimovski

Kuhle

Ramanathan

et al. 2019

Ann Clin Transl Neurol

View full text Add to dashboard Cite

Background Gray matter (GM) pathology is closely associated with physical and cognitive impairment in persons with multiple sclerosis (PwMS). Similarly, serum neurofilament light chain (sNfL) levels are related to MS disease activity and progression. Objectives To assess the cross–sectional and longitudinal associations between sNfL and MRI–derived lesion and brain volume outcomes in PwMS and age–matched healthy controls (HCs). Materials and Methods Forty‐seven HCs and 120 PwMS were followed over 5 years. All subjects underwent baseline and follow–up 3T MRI and sNfL examinations. Lesion volumes (LV) and global, tissue–specific and regional brain volumes were assessed. sNfL levels were analyzed using single molecule array (Simoa) assay and quantified in pg/mL. The associations between sNfL levels and MRI outcomes were investigated using regression analyses adjusted for age, sex, baseline disease modifying treatment (DMT) use and change in DMT over the follow‐up. False discovery rate (FDR)–adjusted q‐values <0.05 were considered significant. Results In PwMS, baseline sNfL was associated with baseline T1‐, T2‐ and gadolinium‐LV (q = 0.002, q = 0.001 and q < 0.001, respectively), but not with their longitudinal changes. Higher baseline sNfL levels were associated with lower baseline deep GM (β = −0.257, q = 0.017), thalamus (β = −0.216, q = 0.0017), caudate (β = −0.263, q = 0.014) and hippocampus (β = −0.267, q = 0.015) volumes. Baseline sNfL was associated with longitudinal decline of deep GM (β = −0.386, q < 0.001), putamen (β = −0.395, q < 0.001), whole brain (β = −0.356, q = 0.002), thalamus (β = −0.272, q = 0.049), globus pallidus (β = −0.284, q = 0.017), and GM (β = −0.264, q = 0.042) volumes. No associations between sNfL and MRI–derived measures were seen in the HCs. Conclusion Higher sNfL levels were associated with baseline LVs and greater development of GM atrophy in PwMS.

show abstract

Section: Discussionsupporting

confidence: 92%

Serum neurofilament light chain levels associations with gray matter pathology: a 5‐year longitudinal study

Jakimovski

Kuhle

Ramanathan

et al. 2019

Ann Clin Transl Neurol

View full text Add to dashboard Cite

show abstract

“…NFL seems to be a robust marker of ongoing disease activity in pwMS. Moreover, NFL levels correlate well with conversion to clinically definitive MS [15,16], increased number of relapses, confirmed disability worsening, treatment and MRI outcomes [17], spinal cord and brain atrophy [4,18,19], and different clinical forms such as radiologically isolated syndrome [20], clinically isolated syndrome (CIS) ( [21], relapsing-remitting MS (RRMS) [16,22,23], and primary progressive MS (PPMS) [24]. NFL levels correlate significantly with the presence of gadolinium enchancing lesions and T2 lesion load [20].…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal Fluid Neurofilament Light Chain Is Associated with Kynurenine Pathway Metabolite Changes in Multiple Sclerosis

Rajda

Galla

Polyák

et al. 2020

IJMS

View full text Add to dashboard Cite

Neurofilament light (NFL) has proved to be a good prognostic factor in multiple sclerosis (MS), as its level is proportionally elevated with extended neuraxonal damage. The involvement of the kynurenine pathway in neuroinflammation has been proved. The precursor of this pathway is the essential amino acid tryptophan, which is catabolized 95% towards kynurenine metabolites. Quinolinic acid (QUIN) within the brain is only produced in activated microglia and macrophages, leading to axonal degeneration via the activation of N-Methyl-D-aspartate receptors. Neopterin is a biomarker for inflammation produced by macrophages. The association of these biomarkers has not previously been investigated. Our aim was to assess whether there is an association of the neurodegenerative biomarker NFL with the markers of neuroinflammation, e.g., kynurenine metabolites and neopterin, in the cerebrospinal fluid (CSF). CSF samples of patients with MS (pwMS; n = 37) and age-matched controls (n = 22) were compared for NFL levels by ELISA, while the kynurenine pathway metabolites tryptophan and neopterin were detected with mass spectrometry. Spearman’s correlation showed that NFL is an independent predictor of neurological disability in the MS group. Significant correlations were found between NFL, neopterin, and QUIN, and between kynurenine and neopterin. Receiver operating characteristic (ROC) curve analysis was used to plot the top three best predictors of MS-related disability that yielded the best specificity and sensitivity. Normalized NFL (AUC: 0.923), QUIN (AUC: 0.803), and neopterin (AUC: 0.843) were the best independent predictors of neurological disability in pwMS. The CSF NFL and CSF QUIN, together with neopterin, were elevated in the CSF of pwMS compared to controls. The combination of the neurodegenerative biomarkers together with biomarkers of neuroinflammation could provide additional information on the underlying pathomechanism of disease activity, which is essential for the identification of patients at risk of developing cumulative disabilities.

show abstract

“…As done in prior analyses examining NfL and WM ( Chitnis et al, 2018 ; Dalla Costa et al, 2019 ; Gravesteijn et al, 2019 ; Kuhle et al, 2019 ), we examined WMH volumes. All linear mixed effect (LME) models were constructed and evaluated using the lme4 and lmerTest packages in the R statistical environment.…”

Section: Methodsmentioning

confidence: 99%

“…Despite the growing usage of NfL as a biomarker, only a modest number of studies have related NfL levels to the markers of white matter (WM) health to which it should be intimately related and mechanistically linked. Results from MS populations have shown that increased levels of NfL in the CSF or blood were related to greater WM hyperintensity (WMH) volumes and gadolinium enhancing lesions ( Chitnis et al, 2018 ; Dalla Costa et al, 2019 ; Disanto et al, 2017 ; Kuhle et al, 2019 ). A similar pattern was found in patients with ischemic stroke ( Tiedt et al, 2018 ) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) ( Gravesteijn et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Serum neurofilament light chain levels are associated with white matter integrity in autosomal dominant Alzheimer's disease

Schultz

Strain

Adedokun

et al. 2020

Neurobiology of Disease

View full text Add to dashboard Cite

Neurofilament light chain (NfL) is a protein that is selectively expressed in neurons. Increased levels of NfL measured in either cerebrospinal fluid or blood is thought to be a biomarker of neuronal damage in neurodegenerative diseases. However, there have been limited investigations relating NfL to the concurrent measures of white matter (WM) decline that it should reflect. White matter damage is a common feature of Alzheimer's disease. We hypothesized that serum levels of NfL would associate with WM lesion volume and diffusion tensor imaging (DTI) metrics cross-sectionally in 117 autosomal dominant mutation carriers (MC) compared to 84 non-carrier (NC) familial controls as well as in a subset ( N = 41) of MC with longitudinal NfL and MRI data. In MC, elevated cross-sectional NfL was positively associated with WM hyperintensity lesion volume, mean diffusivity, radial diffusivity, and axial diffusivity and negatively with fractional anisotropy. Greater change in NfL levels in MC was associated with larger changes in fractional anisotropy, mean diffusivity, and radial diffusivity, all indicative of reduced WM integrity. There were no relationships with NfL in NC. Our results demonstrate that blood-based NfL levels reflect WM integrity and supports the view that blood levels of NfL are predictive of WM damage in the brain. This is a critical result in improving the interpretability of NfL as a marker of brain integrity, and for validating this emerging biomarker for future use in clinical and research settings across multiple neurodegenerative diseases.

show abstract

Prognostic value of serum neurofilaments in patients with clinically isolated syndromes

Cited by 63 publications

References 28 publications

Serum neurofilament light chain levels associations with gray matter pathology: a 5‐year longitudinal study

Serum neurofilament light chain levels associations with gray matter pathology: a 5‐year longitudinal study

Cerebrospinal Fluid Neurofilament Light Chain Is Associated with Kynurenine Pathway Metabolite Changes in Multiple Sclerosis

Serum neurofilament light chain levels are associated with white matter integrity in autosomal dominant Alzheimer's disease

Contact Info

Product

Resources

About