From the Alzheimer Center and Department of Neurology (L.H.H.M., L.D.K., F.J.d.J., J.C.v.S.), Erasmus Medical Center, Rotterdam; Alzheimer Center and Department of Neurology (E.G.V., W.M.v.d.F., Y.A.L.P.), Neurochemistry Laboratory, Department of Clinical Chemistry (M.D.C., C.E.T.), Department of Pathology (A.J.M.R.), and Department of Clinical Genetics (J.C.v.S.), Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
Neurology. 2018 Apr 3;90(14):e1231-e1239. doi: 10.1212/WNL.0000000000005261. Epub 2018 Mar 7.
To examine the clinical value of neurofilament light chain (NfL) and the phospho-tau/total tau ratio (p/t-tau) across the entire frontotemporal dementia (FTD) spectrum in a large, well-defined cohort.
CSF NfL and p/t-tau levels were studied in 361 patients with FTD: 179 behavioral variant FTD, 17 FTD with motor neuron disease (FTD-MND), 36 semantic variant primary progressive aphasia (PPA), 19 nonfluent variant PPA, 4 logopenic variant PPA (lvPPA), 42 corticobasal syndrome, and 64 progressive supranuclear palsy. Forty-five cognitively healthy controls were also included. Definite pathology was known in 68 patients (49 frontotemporal lobar degeneration [FTLD]-TDP, 18 FTLD-tau, 1 FTLD-FUS).
NfL was higher in all diagnoses, except lvPPA (n = 4), than in controls, equally elevated in behavioral variant FTD, semantic variant PPA, nonfluent variant PPA, and corticobasal syndrome, and highest in FTD-MND. The p/t-tau was lower in all clinical groups, except lvPPA, than in controls and lowest in FTD-MND. NfL did not discriminate between TDP and tau pathology, while the p/t-tau ratio had a good specificity (76%) and moderate sensitivity (67%). Both high NfL and low p/t-tau were associated with poor survival (hazard ratio on tertiles 1.7 for NfL, 0.7 for p/t-tau).
NfL and p/t-tau similarly discriminated FTD from controls, but not between clinical subtypes, apart from FTD-MND. Both markers predicted survival and are promising monitoring biomarkers for clinical trials. Of note, p/t-tau, but not NfL, was specific to discriminate TDP from tau pathology in vivo.
This study provides Class III evidence that for patients with cognitive issues, CSF NfL and p/t-tau levels discriminate between those with and without FTD spectrum disorders.
在一个大型、明确界定的队列中，研究神经丝轻链（NfL）和磷酸化 tau/总 tau 比值（p/t-tau）在整个额颞叶痴呆（FTD）谱中的临床价值。
研究了 361 例 FTD 患者的 CSF NfL 和 p/t-tau 水平：179 例行为变异型 FTD、17 例 FTD 伴运动神经元病（FTD-MND）、36 例语义变异型原发性进行性失语症（PPA）、19 例非流利型 PPA、4 例失读型 PPA（lvPPA）、42 例皮质基底节综合征和 64 例进行性核上性麻痹。还纳入了 45 例认知健康对照者。68 例患者（49 例额颞叶变性-TDP、18 例额颞叶痴呆-tau、1 例额颞叶痴呆-FUS）具有明确的病理学。
除 lvPPA（n=4）外，所有诊断的 NfL 均高于对照组，行为变异型 FTD、语义变异型 PPA、非流利型 PPA 和皮质基底节综合征的 NfL 水平相等，而 FTD-MND 的 NfL 水平最高。除 lvPPA 外，所有临床组的 p/t-tau 均低于对照组，而 FTD-MND 的 p/t-tau 最低。NfL 不能区分 TDP 和 tau 病理学，而 p/t-tau 比值具有良好的特异性（76%）和中等的敏感性（67%）。高 NfL 和低 p/t-tau 均与较差的生存相关（NfL 三分位的危险比为 1.7，p/t-tau 为 0.7）。
NfL 和 p/t-tau 同样可以区分 FTD 与对照组，但不能区分 FTD-MND 以外的临床亚型。两种标志物均预测生存，是临床试验有前途的监测生物标志物。值得注意的是，p/t-tau 而非 NfL 可特异性区分体内 TDP 和 tau 病理学。
本研究提供了 III 级证据，表明对于有认知问题的患者，CSF NfL 和 p/t-tau 水平可区分是否患有 FTD 谱障碍。
