Tau and neurofilament light-chain as fluid biomarkers in spinocerebellar ataxia type 3.
Tau and neurofilament light-chain as fluid biomarkers in spinocerebellar ataxia type 3.
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DOI：
10.1111/ene.15373
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发表时间：
2022-08
影响因子：
5.1
通讯作者：
Giunti, Paola
中科院分区：
文献类型：
--
作者：
Garcia-Moreno, Hector;Prudencio, Mercedes;Thomas-Black, Gilbert;Solanky, Nita;Jansen-West, Karen R.;Hanna AL-Shaikh, Rana;Heslegrave, Amanda;Zetterberg, Henrik;Santana, Magda M.;Pereira de Almeida, Luis;Vasconcelos-Ferreira, Ana;Januario, Cristina;Infante, Jon;Faber, Jennifer;Klockgether, Thomas;Reetz, Kathrin;Raposo, Mafalda;Ferreira, Ana F.;Lima, Manuela;Schols, Ludger;Synofzik, Matthis;Hubener-Schmid, Jeannette;Puschmann, Andreas;Gorcenco, Sorina;Wszolek, Zbigniew K.;Petrucelli, Leonard;Giunti, Paola
脊髓小脑性共济失调3型（SCA3）的临床试验将需要生物标志物作为结果测量指标。为了评估总tau蛋白（t - tau）、胶质纤维酸性蛋白（GFAP）、泛素羧基末端水解酶L1 （UCHL1）和神经丝轻链（NfL）作为SCA3、ATXN3突变携带者（n = 143）和对照组（n = 172）的流体生物标志物，在Simoa HD - 1平台上分析了这四种蛋白的血浆浓度。分析了11份ATXN3突变载体脑脊液样本的t - tau和磷酸化tau （p - tau181）。采用转基因SCA3小鼠模型（MJDTg）测量小脑t - tau水平。50岁以下突变携带者的血浆t - tau水平高于对照组，非共济失调体征的清单与共济失调患者的t - tau相关（p = 0.004）。与心性共济失调患者相比，心性共济失调前携带者脑脊液中t - tau和p - tau181浓度更高（p = 0.025和p = 0.014）。与野生型相比，MJDTg小鼠的小脑t - tau仅在疾病的早期阶段升高（p = 0.033）。与对照组相比，GFAP和UCHL1在突变携带者中没有显示出更高的水平。突变携带者的血浆NfL浓度高于对照组，年轻携带者的差异更大。共济失调评定量表是共济失调患者NfL的最强预测因子（p < 0.001）。我们的研究结果表明，tau可能是SCA3早期疾病阶段的一个标志。NfL可以区分突变携带者和对照组，并与不同的临床变量相关。需要进行纵向研究以确认它们在临床试验中作为生物标志物的潜在作用。与对照组相比，年轻ATXN3突变携带者的血浆总tau蛋白（t - tau）升高，与共济失调患者相比，共济失调前受试者的脑脊液t - tau和磷酸化tau181可能更高。此外，在转基因脊髓小脑共济失调3型/ Machado-Joseph病（SCA3/MJD）小鼠模型（MJDTg）中，小脑t - tau水平似乎在疾病的早期阶段升高。因此，tau可能是SCA3/MJD早期阶段的标志物。与对照组相比，ATXN3突变携带者的血浆神经丝轻链（NfL）浓度更高，这种差异在年轻受试者中更为明显。血浆NfL浓度与临床变量相关，是SCA3/MJD的良好候选液体生物标志物。
Clinical trials in spinocerebellar ataxia type 3 (SCA3) will require biomarkers for use as outcome measures. To evaluate total tau (t‐tau), glial fibrillary acidic protein (GFAP), ubiquitin carboxy‐terminal hydrolase L1 (UCHL1) and neurofilament light‐chain (NfL) as fluid biomarkers in SCA3, ATXN3 mutation carriers (n = 143) and controls (n = 172) were clinically assessed, and the plasma concentrations of the four proteins were analysed on the Simoa HD‐1 platform. Eleven ATXN3 mutation carrier cerebrospinal fluid samples were analysed for t‐tau and phosphorylated tau (p‐tau181). A transgenic SCA3 mouse model (MJDTg) was used to measure cerebellar t‐tau levels. Plasma t‐tau levels were higher in mutation carriers below the age of 50 compared to controls, and the Inventory of Non‐Ataxia Signs was associated with t‐tau in ataxic patients (p = 0.004). Pre‐ataxic carriers showed higher cerebrospinal fluid t‐tau and p‐tau181 concentrations compared to ataxic patients (p = 0.025 and p = 0.014, respectively). Cerebellar t‐tau was elevated in MJDTg mice compared to wild‐type (p = 0.033) only in the early stages of the disease. GFAP and UCHL1 did not show higher levels in mutation carriers compared to controls. Plasma NfL concentrations were higher in mutation carriers compared to controls, and differences were greater for younger carriers. The Scale for the Assessment and Rating of Ataxia was the strongest predictor of NfL in ataxic patients (p < 0.001). Our results suggest that tau might be a marker of early disease stages in SCA3. NfL can discriminate mutation carriers from controls and is associated with different clinical variables. Longitudinal studies are required to confirm their potential role as biomarkers in clinical trials. Plasma total tau (t‐tau) is elevated in young ATXN3 mutation carriers compared to controls, and cerebrospinal fluid t‐tau and phosphorylated tau181 may be higher in pre‐ataxic subjects compared to ataxic patients. In addition, cerebellar t‐tau levels seem to be increased in early stages of the disease in a transgenic spinocerebellar ataxia type 3/Machado–Joseph disease (SCA3/MJD) mouse model (MJDTg). Therefore, tau could be a marker of early stages in SCA3/MJD. Plasma neurofilament light‐chain (NfL) concentrations are higher in ATXN3 mutation carriers compared to controls, and such difference is more marked for younger subjects. Plasma NfL concentrations were associated with clinical variables and are a good candidate as a fluid biomarker in SCA3/MJD.
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影响因子：
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通讯作者：
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