P3-251: SERUM NEUROFILAMENT LIGHT CHAIN LEVELS ARE ASSOCIATED WITH CSF NEUROFILAMENT LIGHT CHAIN, COGNITIVE STATUS, AND DISEASE PROGRESSION IN AUTOSOMAL DOMINANT AD

Background: Biochemical and clinical biomarkers correlate with progression rate and disease severity in Parkinson’s disease (PD) but are not sufficiently studied in late PD. Objective: To examine how serum neurofilament light chain (S-NfL) alone or combined with clinical classifications predicts PD outcome in later disease stages. Methods: Eighty-five patients with 7.9±5.1 years of PD duration were included in an observational cohort. Clinical scores were obtained at two separate examinations 8.2±2.0 years apart. S-NfL levels were determined with single molecule array (SiMoA). Five predefined disease progression milestones were assessed. After affirming combination potential of S-NfL and either of two clinical classifications, three combined models were constructed based on these factors and age at onset in different combinations. Results: S-NfL levels showed significant hazard ratios for four out of five disease progression milestones: walking-aid usage (HR 3.5; 95% CI 1.4–8.5), nursing home living (5.1; 2.1–12.5), motor end-stage (6.2; 2.1–17.8), and death (4.1; 1.7–9.7). Higher S-NfL levels were associated with lower ability in activities of daily living and poorer cognition at baseline and/or at follow-up. Combined models showed significantly improved area under receiver operating characteristic curves (0.77–0.91) compared to S-NfL levels alone (0.68–0.71) for predicting the five disease milestones. Conclusion: S-NfL levels stratified patients according to their likelihood to reach clinically relevant progression milestones during this long-term observational study. S-NfL alone reflected motor and social outcomes in later stages of PD. Combining S-NfL with clinical factors was possible and exploratory combined models improved prognostic accuracy.

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Neurofilament light chain (NfL) as a biomarker of hereditary transthyretin-mediated amyloidosis

Neurology ◽

10.1212/wnl.0000000000011090 ◽

2020 ◽

pp. 10.1212/WNL.0000000000011090

Author(s):

Simina Ticau ◽

Gautham V. Sridharan ◽

Shira Tsour ◽

William L. Cantley ◽

Amy Chan ◽

...

Keyword(s):

Disease Progression ◽

Light Chain ◽

Mixed Model ◽

Linear Mixed Model ◽

Controlled Study ◽

Healthy Controls ◽

Class Iii ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

The Impact

ObjectiveTo identify changes in the proteome associated with onset and progression of ATTRv amyloidosis, we performed an observational, case-controlled study which compared proteomes of patients with ATTRv amyloidosis and healthy controls.MethodsPlasma levels of >1,000 proteins were measured in patients with ATTRv amyloidosis with polyneuropathy who received either placebo or patisiran in the APOLLO study and in healthy controls. The impact of patisiran on the time profile of each protein was determined by linear mixed model at 0, 9, and 18 months. Neurofilament light chain (NfL) was further assessed using an orthogonal quantitative approach.ResultsLevels of 66 proteins were significantly changed with patisiran vs placebo, with NfL change most significant (p < 10−20). Analysis of changes in protein levels demonstrated that the proteome of patisiran-treated patients trended toward healthy controls at 18 months. Healthy controls' NfL levels were 4-fold lower than in patients with ATTRv amyloidosis with polyneuropathy (16.3 vs 69.4 pg/mL, effect: −53.1 pg/mL, 95% CI [–60.5 to −45.9]). NfL levels at 18 months increased with placebo (99.5 vs 63.2 pg/mL, 36.3 pg/mL, [16.5–56.1]) and decreased with patisiran treatment (48.8 vs 72.1 pg/mL, −23.3 pg/mL, [–33.4 to −13.1]) from baseline. At 18 months, improvement in modified Neuropathy Impairment Score +7 following patisiran significantly correlated with reduced NfL (R = 0.43, [0.29–0.55]).ConclusionsFindings suggest NfL may serve as a biomarker of nerve damage and polyneuropathy in ATTRv amyloidosis, may enable earlier diagnosis of patients with ATTRv amyloidosis, and facilitate monitoring of disease progression.Classification of evidenceThis study provides Class III evidence that NfL levels may enable earlier diagnosis of polyneuropathy in patients with ATTRv amyloidosis and facilitate monitoring of disease progression.

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P39 Neurofilament light chain polypeptide gene (NEFL) mutations in autosomal dominant or sporadic Charcot-Marie-Tooth disease

Neuromuscular Disorders ◽

10.1016/s0960-8966(11)70058-x ◽

2011 ◽

Vol 21 ◽

pp. S17

Author(s):

Y.-T. Liu ◽

S.M. Murphy ◽

H. Houlden ◽

M.M. Reilly

Keyword(s):

Light Chain ◽

Autosomal Dominant ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Tooth Disease

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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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