Department of Neurology, Otto-von-Guericke University, Leipziger Straße 44, 39120, Magdeburg, Germany.
German Center for Neurodegenerative Diseases (DZNE) Within the Helmholtz Association, Leipziger Straße 44, 39120, Magdeburg, Germany.
J Neurol. 2018 Nov;265(11):2633-2645. doi: 10.1007/s00415-018-9043-0. Epub 2018 Sep 5.
Cerebrospinal fluid (CSF) neurofilament light chain (NfL) has emerged as putative diagnostic biomarker in amyotrophic lateral sclerosis (ALS), but it remains a matter of debate, whether CSF total tau (ttau), tau phosphorylated at threonine 181 (ptau) and the ptau/ttau ratio could serve as diagnostic biomarker in ALS as well. Moreover, the relationship between CSF NfL and tau measures to further axonal and (neuro)degeneration markers still needs to be elucidated. Our analysis included 89 ALS patients [median (range) age 63 (33-83) years, 61% male, disease duration 10 (0.2-190) months] and 33 age- and sex-matched disease controls [60 (32-76), 49%]. NfL was higher and the ptau/ttau ratio was lower in ALS compared to controls [8343 (1795-35,945) pg/ml vs. 1193 (612-2616), H(1) = 70.8, p < 0.001; mean (SD) 0.17 (0.04) vs. 0.2 (0.03), F(1) = 14.3, p < 0.001], as well as in upper motor neuron dominant (UMND, n = 10) compared to classic (n = 46) or lower motor neuron dominant ALS [n = 31; for NfL: 16,076 (7447-35,945) vs. 8205 (2651-35,138) vs. 8057 (1795-34,951)], Z ≥ 2.5, p ≤ 0.01; for the ptau/ttau ratio: [0.13 (0.04) vs. 0.17 (0.04) vs. 0.18 (0.03), p ≤ 0.02]. In ALS, NfL and the ptau/ttau ratio were related to corticospinal tract (CST) fractional anisotropy (FA) and radial diffusivity (ROI-based approach and whole-brain voxelwise analysis). Factor analysis of mixed data revealed a co-variance pattern between NfL (factor load - 0.6), the ptau/ttau ratio (0.7), CST FA (0.8) and UMND ALS phenotype (- 2.8). NfL did not relate to any further neuroaxonal injury marker (brain volumes, precentral gyrus thickness, peripheral motor amplitudes, sonographic cross-sectional nerve area), but a lower ptau/ttau ratio was associated with whole-brain gray matter atrophy and widespread white matter integrity loss. Higher NfL baseline levels were associated with greater UMN disease burden, more rapid disease progression, a twofold to threefold greater hazard of death and shorter survival times. The findings that higher CSF NfL levels and a reduced ptau/ttau ratio are more associated with clinical UMN involvement and with reduced CST FA offer strong converging evidence that both are markers of central motor degeneration. Furthermore, NfL is a marker of poor prognosis, while a low ptau/ttau ratio indicates extramotor pathology in ALS.
脑脊液（CSF）神经丝轻链（NfL）已成为肌萎缩侧索硬化症（ALS）的潜在诊断生物标志物，但 CSF 总 tau（ttau）、tau 磷酸化在苏氨酸 181 位（ptau）和 ptau/ttau 比值是否也可作为 ALS 的诊断生物标志物仍存在争议。此外，CSF NfL 与 tau 测量值之间的关系仍需要进一步阐明，以进一步了解轴突和（神经）变性标志物。我们的分析包括 89 名 ALS 患者[中位（范围）年龄 63（33-83）岁，61%为男性，病程 10（0.2-190）个月]和 33 名年龄和性别匹配的疾病对照者[60（32-76）岁，49%为男性]。与对照组相比，ALS 患者的 NfL 水平较高，ptau/ttau 比值较低[8343（1795-35945）pg/ml 比 1193（612-2616）pg/ml，H（1）=70.8，p<0.001；平均值（标准差）0.17（0.04）比 0.2（0.03），F（1）=14.3，p<0.001]，上运动神经元优势（UMND，n=10）与经典型（n=46）或下运动神经元优势 ALS[n=31；NfL：16076（7447-35945）比 8205（2651-35138）比 8057（1795-34951）]相比，Z 值≥2.5，p 值≤0.01；ptau/ttau 比值：[0.13（0.04）比 0.17（0.04）比 0.18（0.03），p 值≤0.02]。在 ALS 患者中，NfL 和 ptau/ttau 比值与皮质脊髓束（CST）各向异性分数（FA）和放射状弥散（基于 ROI 和全脑体素分析）相关。混合数据的因子分析显示，NfL（因子负荷-0.6）、ptau/ttau 比值（0.7）、CST FA（0.8）和 UMND ALS 表型（-2.8）之间存在协方差模式。NfL 与任何进一步的神经轴突损伤标志物（脑体积、中央前回厚度、周围运动幅度、超声横截面积神经面积）均无相关性，但较低的 ptau/ttau 比值与全脑灰质萎缩和广泛的白质完整性丧失有关。较高的 NfL 基线水平与 UMN 疾病负担更大、疾病进展更快、死亡风险增加两倍至三倍以及生存时间更短相关。更高的 CSF NfL 水平和降低的 ptau/ttau 比值与更明显的临床 UMN 受累和 CST FA 降低更相关，这有力地证明了它们都是中央运动区退行性变的标志物。此外，NfL 是预后不良的标志物，而低 ptau/ttau 比值则表明 ALS 存在运动外病理学。
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