神经丝轻链作为遗传性转甲状腺素蛋白介导的淀粉样变性的生物标志物。
Neurofilament Light Chain as a Biomarker of Hereditary Transthyretin-Mediated Amyloidosis.
机构信息
From Alnylam Pharmaceuticals (S.T., G.V.S., S.T., W.L.C., A.C., J.A.G., D.E., E.A., K.F., A.V., P.N.) , Cambridge, MA; MRC Centre for Neuromuscular Diseases (M.M.R.), UCL Queen Square Institute of Neurology, London, UK; AP-HP (D.A.), Université Paris-Saclay, CHU Bicêtre, INSERM U1195, Le Kremlin Bicêtre, France; and Department of Neurology (M.P.), Johns Hopkins University School of Medicine, Baltimore, MD.
出版信息
Neurology. 2021 Jan 19;96(3):e412-e422. doi: 10.1212/WNL.0000000000011090. Epub 2020 Oct 21.
OBJECTIVE
To identify changes in the proteome associated with onset and progression of hereditary transthyretin-mediated (hATTR) amyloidosis, also known as ATTRv amyloidosis, we performed an observational, case-controlled study that compared proteomes of patients with ATTRv amyloidosis and healthy controls.
METHODS
Plasma levels of >1,000 proteins were measured in patients with ATTRv amyloidosis with polyneuropathy who received either placebo or patisiran in a Phase 3 study of patisiran (APOLLO), and in healthy controls. The effect 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 with an orthogonal quantitative approach.
RESULTS
Levels of 66 proteins were significantly changed with patisiran vs placebo, with NfL change most significant ( < 10). Analysis of changes in protein levels demonstrated that the proteome of patients treated with patisiran trended toward that of healthy controls at 18 months. Healthy controls' NfL levels were 4-fold lower than in patients with ATTRv amyloidosis with polyneuropathy (16.3 pg/mL vs 69.4 pg/mL, effect -53.1 pg/mL [95% confidence interval -60.5 to -45.9]). NfL levels at 18 months increased with placebo (99.5 pg/mL vs 63.2 pg/mL, effect 36.3 pg/mL [16.5-56.1]) and decreased with patisiran treatment (48.8 pg/mL vs 72.1 pg/mL, effect -23.3 pg/mL [-33.4 to -13.1]) from baseline. At 18 months, improvement in modified Neuropathy Impairment Score +7 score after patisiran treatment significantly correlated with reduced NfL ( = 0.43 [0.29-0.55]).
CONCLUSIONS
Findings suggest that NfL may serve as a biomarker of nerve damage and polyneuropathy in ATTRv amyloidosis, enable earlier diagnosis of patients with ATTRv amyloidosis, and facilitate monitoring of disease progression.
CLASSIFICATION OF EVIDENCE
This 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.
目的
为了确定与遗传性转甲状腺素蛋白介导（hATTR）淀粉样变性（也称为 ATTRv 淀粉样变性）发病和进展相关的蛋白质组变化，我们进行了一项观察性、病例对照研究，比较了接受 patisiran 治疗的 ATTRv 淀粉样变性患者和健康对照者的蛋白质组。
方法
在 patisiran（APOLLO）的 3 期研究中，我们测量了接受安慰剂或 patisiran 治疗的伴有多发性神经病的 ATTRv 淀粉样变性患者以及健康对照者的 >1000 种蛋白质的血浆水平。通过线性混合模型在 0、9 和 18 个月时确定 patisiran 对每种蛋白质时间曲线的影响。用正交定量方法进一步评估神经丝轻链（NfL）。
结果
与安慰剂相比，66 种蛋白质的水平有显著变化，其中 NfL 变化最显著（<10）。蛋白质水平变化的分析表明，接受 patisiran 治疗的患者的蛋白质组在 18 个月时趋于健康对照者。健康对照者的 NfL 水平比伴有多发性神经病的 ATTRv 淀粉样变性患者低 4 倍（16.3pg/ml 比 69.4pg/ml，效应-53.1pg/ml[95%置信区间-60.5 至-45.9]）。18 个月时，安慰剂组的 NfL 水平升高（99.5pg/ml 比 63.2pg/ml，效应 36.3pg/ml[16.5-56.1]），patisiran 治疗组降低（48.8pg/ml 比 72.1pg/ml，效应-23.3pg/ml[-33.4 至-13.1]）。18 个月时，接受 patisiran 治疗后改良神经病变损害评分+7 评分的改善与 NfL 降低显著相关（=0.43[0.29-0.55]）。
结论
研究结果表明，NfL 可能作为 ATTRv 淀粉样变性神经损伤和多发性神经病的生物标志物，有助于 ATTRv 淀粉样变性患者的早期诊断，并有助于监测疾病进展。
证据分类
这项研究提供了 III 级证据，表明 NfL 水平可能有助于 ATTRv 淀粉样变性患者多发性神经病的早期诊断，并有助于监测疾病进展。
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