Neurofilament light chain and α-synuclein RT-QuIC as differential diagnostic biomarkers in parkinsonisms and related syndromes

AbstractNeurofilament light chain (NfL) and α-synuclein oligomeric seeds (α-syn-s) are promising biomarkers for patients with parkinsonism. We assessed their performance in discriminating Parkinson disease (PD) from atypical parkinsonisms (APDs) and evaluated the association between NfL levels and clinical measures of disease severity. We measured NfL in cerebrospinal fluid (CSF) and/or plasma by immunoassays and α-syn-s in CSF by real-time quaking-induced conversion (RT-QuIC) in patients with PD (n = 153), multiple system atrophy (MSA) (n = 80), progressive supranuclear palsy/cortico-basal syndrome (PSP/CBS) (n = 58), dementia with Lewy bodies (n = 64), isolated REM-sleep behaviour disorder (n = 19), and isolated autonomic failure (n = 30). Measures of disease severity included disease duration, UPDRS-III score, Hoehn and Yahr stage, orthostatic hypotension, MMSE score, and CSF amyloid-beta profile. Both CSF NfL (cNfL) and plasma NfL (pNfL) levels were markedly elevated in APDs, and allowed differentiation with PD (vs. APDs, cNfL AUC 0.96; pNfL AUC 0.95; vs. MSA cNfL AUC 0.99; pNfL AUC 0.97; vs. PSP/CBS cNfL AUC 0.94; pNfL AUC 0.94). RT-QuIC detected α-syn-s in 91.4% of PD, but only 2.5% of APDs (all MSA). In PD/PDD, motor scales significantly correlated with cNfL levels. Although pNfL and both cNfL and α-syn-s accurately distinguished PD from APDs, the combined assessment of CSF markers provided a higher diagnostic value (PD vs. APDs AUC 0.97; vs. MSA AUC 0.97; vs. PSP/CBS AUC 0.99) than RT-QuIC alone (p = 0.047 vs. APDs; p = 0.002 vs MSA; p = 0.007 vs PSP/CBS), or cNfL alone (p = 0.011 vs. APDs; p = 0.751 vs MSA; p = 0.0001 vs. PSP/CBS). The results support the use of these assays in specialised clinics.

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Plasma glial fibrillary acidic protein and neurofilament light chain are measures of disease severity in semantic variant primary progressive aphasia

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2020-325085 ◽

2020 ◽

pp. jnnp-2020-325085

Author(s):

Carolin Heller ◽

Elise Chan ◽

Martha S Foiani ◽

Emily Todd ◽

Lucy L Russell ◽

...

Keyword(s):

Glial Fibrillary Acidic Protein ◽

Disease Severity ◽

Light Chain ◽

Primary Progressive Aphasia ◽

Acidic Protein ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Progressive Aphasia ◽

Primary Progressive ◽

Semantic Variant

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Plasma Neurofilament Light Chain Predicts Cognitive Progression in Prodromal and Clinical Dementia with Lewy Bodies

Journal of Alzheimer s Disease ◽

10.3233/jad-210342 ◽

2021 ◽

pp. 1-7

Author(s):

Andrea Pilotto ◽

Alberto Imarisio ◽

Claudia Carrarini ◽

Mirella Russo ◽

Stefano Masciocchi ◽

...

Keyword(s):

Light Chain ◽

Neurological Disorders ◽

Dementia With Lewy Bodies ◽

Neuronal Damage ◽

Lewy Bodies ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Predict Disease Progression

Plasma neurofilament light chain (NfL) is a marker of neuronal damage in different neurological disorders and might predict disease progression in dementia with Lewy bodies (DLB). The study enrolled 45 controls and 44 DLB patients (including 17 prodromal cases) who underwent an extensive assessment at baseline and at 2 years follow-up. At baseline, plasma NfL levels were higher in both probable DLB and prodromal cases compared to controls. Plasma NfL emerged as the best predictor of cognitive decline compared to age, sex, and baseline severity variables. The study supports the role of plasma NfL as a useful prognostic biomarker from the early stages of DLB.

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Neurofilament light chain levels correlate with clinical measures in CLN3 disease

Genetics in Medicine ◽

10.1038/s41436-020-01035-3 ◽

2020 ◽

Author(s):

An N. Dang Do ◽

Ninet Sinaii ◽

Ruturaj R. Masvekar ◽

Eva H. Baker ◽

Audrey E. Thurm ◽

...

Keyword(s):

Light Chain ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Cln3 Disease ◽

Clinical Measures

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Blood neurofilament light chain in Parkinson disease and atypical parkinsonisms

Medicine ◽

10.1097/md.0000000000021871 ◽

2020 ◽

Vol 99 (40) ◽

pp. e21871

Author(s):

HongZhou Wang ◽

WanHua Wang ◽

HaiCun Shi ◽

LiJian Han ◽

PingLei Pan

Keyword(s):

Parkinson Disease ◽

Light Chain ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Atypical Parkinsonisms

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Plasma Neurofilament Light Chain predicts cognitive progression in prodromal and clinical dementia with Lewy Bodies

10.1101/2021.03.19.21253993 ◽

2021 ◽

Author(s):

Andrea Pilotto ◽

Alberto Imarisio ◽

Claudia Carrarini ◽

Mirella Russo ◽

Stefano Masciocchi ◽

...

Keyword(s):

Light Chain ◽

Neurological Disorders ◽

Dementia With Lewy Bodies ◽

Neuronal Damage ◽

Lewy Bodies ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Predict Disease Progression

Plasma neurofilament light chain (NfL) is a marker of neuronal damage in different neurological disorders and might predict disease progression in dementia with Lewy bodies (DLB). The study enrolled 45 controls and 44 DLB patients (including 17 prodromal cases) who underwent an extensive assessment at baseline and at 2 years follow-up. At baseline, plasma NfL levels were higher in both probable DLB and prodromal cases compared to controls. Plasma NfL emerged as the best predictor of cognitive decline compared to age, sex and baseline severity variables. The study supports the role of plasma NfL as a useful prognostic biomarker from the early stages of DLB.

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Neurofilament Light Chain Predicts Disease Severity and Progression in Multiple System Atrophy

Movement Disorders ◽

10.1002/mds.28847 ◽

2021 ◽

Author(s):

Lingyu Zhang ◽

Bei Cao ◽

Yanbing Hou ◽

Xiaojing Gu ◽

Qianqian Wei ◽

...

Keyword(s):

Multiple System Atrophy ◽

Disease Severity ◽

Light Chain ◽

Neurofilament Light Chain ◽

Neurofilament Light

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High serum neurofilament light chain normalizes after hematopoietic stem cell transplantation for MS

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000000598 ◽

2019 ◽

Vol 6 (5) ◽

pp. e598 ◽

Cited By ~ 13

Author(s):

Simon Thebault ◽

Daniel R. Tessier ◽

Hyunwoo Lee ◽

Marjorie Bowman ◽

Amit Bar-Or ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Disease Severity ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Light Chain ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Hematopoietic Stem

ObjectiveTo evaluate neurofilament light chain (NfL) levels in serum and CSF of patients with aggressive MS pre- and post-treatment with immunoablation followed by autologous hematopoietic stem cell transplantation (IAHSCT) and examine associations with clinical and MRI outcomes.MethodsPaired serum and CSF in addition to MRI and clinical measures were collected on 23 patients with MS at baseline and 1 and 3 years post-IAHSCT. An additional 33 sera and CSF pairs were taken from noninflammatory neurologic controls. NfL levels were quantitated using the Simoa platform (Quanterix).ResultsBaseline MS NfL levels were significantly elevated relative to controls in serum (p = 0.001) and CSF (p = 0.001). Following IAHSCT, high pretreatment NfL levels significantly reduced in serum (p = 0.0023) and CSF (p = 0.0068) and were not significantly different from controls. Serum and CSF NfL levels highly correlated (r = 0.81, p < 0.0001). Baseline NfL levels were associated with worse pretreatment disease measures (Expanded Disability Status Scale [EDSS], relapses, MRI lesions, and MR spectroscopy (MRS) N-acetylaspartate/creatine). Elevated baseline NfL levels were associated with persistently worse indices of disease burden post-IAHSCT (sustained EDSS progression, cognition, quality of life, T1 and T2 lesion volumes, MRS, and brain atrophy).ConclusionThese data substantiate that serum and CSF NfL levels reflect disease severity and treatment response in patients with MS and may therefore be a useful biomarker. Baseline serum levels associated with markers of pretreatment disease severity and post-treatment outcomes.Classification of evidenceThis study provides Class II evidence that for patients with aggressive MS, serum NfL levels are associated with disease severity.

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CSF neurofilament light chain and phosphorylated tau 181 predict disease progression in PSP

Neurology ◽

10.1212/wnl.0000000000004859 ◽

2017 ◽

Vol 90 (4) ◽

pp. e273-e281 ◽

Cited By ~ 31

Author(s):

Julio C. Rojas ◽

Jee Bang ◽

Iryna V. Lobach ◽

Richard M. Tsai ◽

Gil D. Rabinovici ◽

...

Keyword(s):

Disease Progression ◽

Disease Severity ◽

Light Chain ◽

Rating Scale ◽

Superior Cerebellar Peduncle ◽

Phosphorylated Tau ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Phosphorylated Tau 181 ◽

Predict Disease Progression

ObjectiveTo determine the ability of CSF biomarkers to predict disease progression in progressive supranuclear palsy (PSP).MethodsWe compared the ability of baseline CSF β-amyloid1–42, tau, phosphorylated tau 181 (p-tau), and neurofilament light chain (NfL) concentrations, measured by INNO-BIA AlzBio3 or ELISA, to predict 52-week changes in clinical (PSP Rating Scale [PSPRS] and Schwab and England Activities of Daily Living [SEADL]), neuropsychological, and regional brain volumes on MRI using linear mixed effects models controlled for age, sex, and baseline disease severity, and Fisher F density curves to compare effect sizes in 50 patients with PSP. Similar analyses were done using plasma NfL measured by single molecule arrays in 141 patients.ResultsHigher CSF NfL concentration predicted more rapid decline (biomarker × time interaction) over 52 weeks in PSPRS (p = 0.004, false discovery rate–corrected) and SEADL (p = 0.008), whereas lower baseline CSF p-tau predicted faster decline on PSPRS (p = 0.004). Higher CSF tau concentrations predicted faster decline by SEADL (p = 0.004). The CSF NfL/p-tau ratio was superior for predicting change in PSPRS, compared to p-tau (p = 0.003) or NfL (p = 0.001) alone. Higher NfL concentrations in CSF or blood were associated with greater superior cerebellar peduncle atrophy (fixed effect, p ≤ 0.029 and 0.008, respectively).ConclusionsBoth CSF p-tau and NfL correlate with disease severity and rate of disease progression in PSP. The inverse correlation of p-tau with disease severity suggests a potentially different mechanism of tau pathology in PSP as compared to Alzheimer disease.

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Plasma neurofilament light chain concentration in the inherited peripheral neuropathies

Neurology ◽

10.1212/wnl.0000000000004932 ◽

2018 ◽

Vol 90 (6) ◽

pp. e518-e524 ◽

Cited By ~ 61

Author(s):

Åsa Sandelius ◽

Henrik Zetterberg ◽

Kaj Blennow ◽

Rocco Adiutori ◽

Andrea Malaspina ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Disease Severity ◽

Light Chain ◽

Cross Sectional Study ◽

Healthy Controls ◽

Neurofilament Light Chain ◽

Cross Sectional ◽

Neurofilament Light ◽

Charcot Marie Tooth Disease ◽

Inherited Neuropathies

ObjectiveTo perform a cross-sectional study to determine whether plasma neurofilament light chain (NfL) concentration is elevated in patients with Charcot-Marie-Tooth disease (CMT) and if it correlates with disease severity.MethodsBlood samples were collected from 75 patients with CMT and 67 age-matched healthy controls over a 1-year period. Disease severity was measured using the Rasch modified CMT Examination and neuropathy scores. Plasma NfL concentration was measured using an in-house-developed Simoa assay.ResultsPlasma NfL concentration was significantly higher in patients with CMT (median 26.0 pg/mL) compared to healthy controls (median 14.6 pg/mL, p < 0.0001) and correlated with disease severity as measured using the Rasch modified CMT examination (r = 0.43, p < 0.0001) and neuropathy (r = 0.37, p = 0.044) scores. Concentrations were also significantly higher when subdividing patients by genetic subtype (CMT1A, SPTLC1, and GJB1) or into demyelinating or axonal forms compared to healthy controls.ConclusionThere are currently no validated blood biomarkers for peripheral neuropathy. The significantly raised plasma NfL concentration in patients with CMT and its correlation with disease severity suggest that plasma NfL holds promise as a biomarker of disease activity, not only for inherited neuropathies but for peripheral neuropathy in general.

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