Clinical Memory Research Unit, Lund University, Malmö, Sweden; Alzheimer Center Amsterdam, Department of Neurology, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands.
Alzheimer Center Amsterdam, Department of Neurology, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands; Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands.
Lancet Neurol. 2022 Aug;21(8):726-734. doi: 10.1016/S1474-4422(22)00168-5. Epub 2022 May 25.
Deposition of tau aggregates is a pathological hallmark of Alzheimer's disease that is closely linked both spatially and temporally to emergence of neurodegeneration and manifestation of clinical symptoms. There is an urgent need for accurate PET, CSF, and plasma biomarkers of tau pathology to improve the diagnostic process in clinical practice and the selection of participants and monitoring of treatment effects in trials.
Innovative second-generation tau-PET tracers with high affinity and selectivity to tau pathology in Alzheimer's disease have enabled detection of tau pathology in medial temporal lobe subregions that are affected in the earliest disease stages. Furthermore, novel but common tau spreading subtypes have been discovered using tau-PET, suggesting much greater interindividual differences in the distribution of tau pathology across the brain than previously assumed. In the CSF biomarker field, novel phosphorylated tau (p-tau) assays have been introduced that better reflect tau tangle load than established CSF biomarkers of tau pathology. The advent of cost-effective and accessible blood-based biomarkers for tau pathophysiology (ie, p-tau181, p-tau217, and p-tau231) might transform the Alzheimer's disease field, as these biomarkers correlate with post-mortem Alzheimer's disease pathology, differentiate Alzheimer's disease from other types of dementia, and predict future progression from normal cognition and mild cognitive impairment to Alzheimer's disease. In controlled investigational settings, improvements in tau-PET and biofluid p-tau markers have led to earlier disease detection, more accurate diagnostic methods, and refinement of prognosis. The anti-tau therapy landscape is rapidly evolving, with multiple ongoing phase 1 and 2 trials of post-translational modification of tau, tau immunotherapy, tau aggregation inhibitors, and targeting production of tau and reduction of intracellular tau levels. Neuroimaging and biofluid tau markers hold potential for optimising such clinical trials by augmenting participant selection, providing evidence of target engagement, and monitoring treatment efficacy. WHERE NEXT?: Major challenges to overcome are the high cost of tau-PET, partial sensitivity to detect early-stage Alzheimer's disease pathology, and off-target tracer binding. Prospective validation studies of biofluid p-tau markers are needed, and assay-related preanalytical and analytical factors need further refinement. Future studies should focus on demonstrating the diagnostic and prognostic accuracy of tau biomarkers-blood-based markers in particular-in non-tertiary settings, such as primary care, which is characterised by a diverse population with medical comorbidities. Large-scale head-to-head studies are needed across different stages of Alzheimer's disease to determine which tau biomarker is optimal in various clinical scenarios, such as early diagnosis, differential diagnosis, and prognosis, and for aspects of clinical trial design, such as proving target engagement, optimising participant selection, and refining monitoring of treatment effects.
tau 聚集物的沉积是阿尔茨海默病的病理标志，它在空间和时间上与神经退行性变的出现和临床症状的表现密切相关。迫切需要准确的 tau 病理学 PET、CSF 和血浆生物标志物，以改善临床实践中的诊断过程，以及临床试验中参与者的选择和治疗效果的监测。
具有高亲和力和对阿尔茨海默病 tau 病理学选择性的创新第二代 tau-PET 示踪剂，使我们能够检测到内侧颞叶亚区的 tau 病理学，这些亚区在疾病的早期阶段就受到了影响。此外，tau-PET 还发现了新的但常见的 tau 扩散亚型，这表明 tau 病理学在大脑中的分布个体间差异比以前假设的要大得多。在 CSF 生物标志物领域，已经引入了新的磷酸化 tau(p-tau)检测方法，这些方法比现有的 tau 病理学 CSF 标志物能更好地反映 tau 缠结负荷。具有成本效益和易于获得的 tau 生理病理学血液生物标志物（即 p-tau181、p-tau217 和 p-tau231）的出现可能会改变阿尔茨海默病领域，因为这些标志物与死后阿尔茨海默病病理学相关，可将阿尔茨海默病与其他类型的痴呆症区分开来，并可预测从正常认知和轻度认知障碍到阿尔茨海默病的未来进展。在对照研究环境中，tau-PET 和生物流体 p-tau 标志物的改进导致了更早的疾病检测、更准确的诊断方法和预后的改善。tau 疗法领域正在迅速发展，多个正在进行的翻译后修饰 tau、tau 免疫疗法、tau 聚集抑制剂以及靶向 tau 产生和减少细胞内 tau 水平的临床试验。神经影像学和生物流体 tau 标志物有可能通过增加参与者的选择、提供目标参与的证据以及监测治疗效果，优化此类临床试验。
下一步是什么？需要克服的主要挑战是 tau-PET 成本高、对早期阿尔茨海默病病理的敏感性部分以及非靶向示踪剂结合。需要对生物流体 p-tau 标志物进行前瞻性验证研究，进一步改进与检测相关的分析前和分析因素。未来的研究应集中在证明 tau 生物标志物-特别是血液标志物-在非三级环境中的诊断和预后准确性，例如初级保健，初级保健的特点是人群多样化，伴有医疗合并症。需要在不同阶段的阿尔茨海默病中进行大规模的头对头研究，以确定哪种 tau 生物标志物在各种临床情况下是最佳的，例如早期诊断、鉴别诊断和预后，以及临床试验设计的各个方面，例如证明目标参与、优化参与者选择和改进治疗效果监测。
