From the Departments of Neurology (C.P., E.W., A.M.B., S.K., J.L., G.U.H.), Nuclear Medicine (S.W., C.F., S.H., J.S., S.S., J.G., A.F., G.B., S.L., N.L.A., P.B., M.B.), and Psychiatry and Psychotherapy (B.-S.R., R.P.) and the Institutes for Stroke and Dementia Research (N.F.) and Neuroradiology (B.-S.R.), University Hospital, LMU Munich, Germany; Munich Cluster for Systems Neurology (C.P., N.F., S.K., P.B., R.P., C.H., M.B., J.L.), SyNergy, Germany; German Center for Neurodegenerative Diseases (C.P., E.W., A.M.B., S.K., B.N., B.-S.R., R.P., C.H., M.B., J.L., G.U.H.), DZNE-Munich, Germany; Department of Nuclear Medicine (O.S., H.B.), Leipzig University Medical Centre; Department of Psychiatry and Psychotherapy (R.R.), University of Regensburg, Germany; Life Molecular Imaging GmbH (A.W.S.), Berlin, Germany; Sheffield Institute for Translational Neuroscience (SITraN) (B.-S.R., R.P.), University of Sheffield, United Kingdom; Ageing Epidemiology Research Unit (AGE) (R.P.), School of Public Health, Imperial College London, United Kingdom; and Chair of Metabolic Biochemistry (C.H.), Biomedical Center (BMC), Ludwig-Maximilians-Universität LMU, Munich, Germany.
Neurology. 2024 Jan 9;102(1):e207901. doi: 10.1212/WNL.0000000000207901. Epub 2023 Dec 14.
Corticobasal syndrome (CBS) with underlying 4-repeat tauopathy is a progressive neurodegenerative disease characterized by declining cognitive and motor functions. Biomarkers for assessing pathologic brain changes in CBS including tau-PET, 18 kDa translocator protein (TSPO)-PET, structural MRI, neurofilament light chain (NfL), or glial fibrillary acidic protein (GFAP) have recently been evaluated for differential diagnosis and disease staging, yet their association with disease trajectories remains unclear. Therefore, we performed a head-to-head comparison of neuroimaging (tau-PET, TSPO-PET, structural MRI) and plasma biomarkers (NfL, GFAP) as prognostic tools for longitudinal clinical trajectories in β-amyloid (Aβ)-negative CBS.
We included patients with clinically diagnosed Aβ-negative CBS with clinical follow-up data who underwent baseline structural MRI and plasma-NfL analysis for assessing neurodegeneration, [F]PI-2620-PET for assessing tau pathology, [F]GE-180-PET for assessing microglia activation, and plasma-GFAP analysis for assessing astrocytosis. To quantify tau and microglia load, we assessed summary scores of whole-brain, cortical, and subcortical PET signal. For structural MRI analysis, we quantified subcortical and cortical gray matter volume. Plasma NfL and GFAP values were assessed using Simoa-based immunoassays. Symptom progression was determined using a battery of cognitive and motor tests (i.e., Progressive Supranuclear Palsy Rating Scale [PSPRS]). Using linear mixed models, we tested whether the assessed biomarkers at baseline were associated with faster symptom progression over time (i.e., time × biomarker interaction).
Overall, 21 patients with Aβ-negative CBS with ∼2-year clinical follow-up data were included. Patients with CBS with more widespread global tau-PET signal showed faster clinical progression (PSPRS: B/SE = 0.001/0.0005, = 0.025), driven by cortical rather than subcortical tau-PET. By contrast, patients with higher global [F]GE-180-PET readouts showed slower clinical progression (PSPRS: B/SE = -0.056/0.023, = 0.019). No association was found between gray matter volume and clinical progression. Concerning fluid biomarkers, only higher plasma-NfL (PSPRS: B/SE = 0.176/0.046, < 0.001) but not GFAP was associated with faster clinical deterioration. In a subsequent sensitivity analysis, we found that tau-PET, TSPO-PET, and plasma-NfL showed significant interaction effects with time on clinical trajectories when tested in the same model.
[F]PI-2620 tau-PET, [F]GE-180 TSPO-PET, and plasma-NfL show prognostic potential for clinical progression in patients with Aβ-negative CBS with probable 4-repeat tauopathy, which can be useful for clinical decision-making and stratifying patients in clinical trials.
皮质基底节综合征（CBS）伴潜在的 4 重复tau 病是一种进行性神经退行性疾病，其特征为认知和运动功能逐渐下降。评估皮质基底节综合征中病理性脑改变的生物标志物，包括 tau-PET、18 kDa 转位蛋白（TSPO）-PET、结构磁共振成像（MRI）、神经丝轻链（NfL）或胶质纤维酸性蛋白（GFAP），最近已被用于鉴别诊断和疾病分期，但它们与疾病轨迹的关系仍不清楚。因此，我们进行了一项头对头比较，比较了神经影像学（tau-PET、TSPO-PET、结构 MRI）和血浆生物标志物（NfL、GFAP）作为β-淀粉样蛋白（Aβ）阴性 CBS 纵向临床轨迹的预后工具。
我们纳入了临床诊断为 Aβ 阴性 CBS 且具有基线后临床随访数据的患者，这些患者接受了基线结构 MRI 和血浆 NfL 分析以评估神经退行性变，[F]PI-2620-PET 以评估 tau 病理学，[F]GE-180-PET 以评估小胶质细胞激活，以及血浆 GFAP 分析以评估星形胶质细胞增生。为了量化 tau 和小胶质细胞负荷，我们评估了全脑、皮质和皮质下 PET 信号的综合评分。对于结构 MRI 分析，我们量化了皮质下和皮质灰质体积。使用基于 Simoa 的免疫测定法评估血浆 NfL 和 GFAP 值。使用一系列认知和运动测试（即进行性核上性麻痹评分量表[PSPRS]）来确定症状进展。使用线性混合模型，我们测试了基线时评估的生物标志物是否与随时间的更快症状进展（即时间×生物标志物相互作用）相关。
总共纳入了 21 例 Aβ 阴性 CBS 患者，具有约 2 年的临床随访数据。具有更广泛的皮质基底节综合征全脑 tau-PET 信号的患者表现出更快的临床进展（PSPRS：B/SE = 0.001/0.0005， = 0.025），这主要是由皮质而不是皮质下 tau-PET 驱动的。相比之下，具有更高的全脑[F]GE-180-PET 读数的患者表现出较慢的临床进展（PSPRS：B/SE = -0.056/0.023， = 0.019）。灰质体积与临床进展之间没有关联。关于液体生物标志物，只有较高的血浆 NfL（PSPRS：B/SE = 0.176/0.046， < 0.001）与更快的临床恶化相关，而 GFAP 则不然。在随后的敏感性分析中，我们发现当在同一模型中测试时，tau-PET、TSPO-PET 和血浆 NfL 与临床轨迹的时间具有显著的相互作用效应。
[F]PI-2620 tau-PET、[F]GE-180 TSPO-PET 和血浆 NfL 对 Aβ 阴性 CBS 伴可能的 4 重复 tau 病患者的临床进展具有预后潜力，这对于临床决策和临床试验中的患者分层可能有用。
