Lessons Learned in Time-Is Neurodegeneration Still Something Unpredictable?
Lessons Learned in Time-Is Neurodegeneration Still Something Unpredictable?
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及时吸取的教训——神经退行性变仍然是不可预测的吗？
DOI：
10.1007/s13311-023-01412-1
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Hu,WilliamT
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作者：
Hu,WilliamT
自美国国立卫生研究院生物标志物定义工作组提出疾病相关生物标志物的理想特征以加快和告知治疗学研究以来，已经有25年了。在神经退行性疾病中，量化或可视化与疾病发病机制相关的肽和聚集物一直是生物标志物开发的核心原则。在阿尔茨海默病（AD）病因学生物标志物的成熟和应用方面取得了无与伦比的成功。尽管研究人员在十年前庆祝阿尔茨海默病神经病理学与正电子发射断层扫描（PET）或脑脊液（CSF）生物标志物[2]之间的一致关联，但我们现在已经看到美国食品和药物管理局（FDA）批准了不溶性阿尔茨海默病蛋白PET成像、可溶性CSF阿尔茨海默病蛋白和抗淀粉样蛋白疾病修饰疗法（DMTs）。这些进步并非没有陷阱或警告，其中许多是通过社会价值而不是科学影响来判断的。然而，即使在病因学诊断和治疗方面取得了适度的成功，也会使阿尔茨海默病从一种不稳定的临床综合征转变为一种真正的分子疾病。与轻率的发现努力相比，在识别和瞄准淀粉样蛋白方面的刻意匆忙似乎产生了合理的投资回报，后者往往缺乏准确性和精确性，或者两者兼而有之。然而，淀粉样蛋白只是将衰老与AD神经病理联系起来的众多病理变化之一，淀粉样蛋白模板是否可以应用于AD和非AD神经退行性疾病的其他聚集蛋白仍然存在争议。与脑脊液tau水平与AD神经病理之间的中度关系不同，脑脊液中a-突触核蛋白（a-syn）、tau和TDP-43的水平在很大程度上与帕金森病（PD）和与tau （FTLD-Tau）或TDP-43 （FTLD-TDP）相关的额颞叶变性中的脑蛋白聚集不一致。这些发现是否强化了人们不应该通过相同的治疗方式靶向细胞外（淀粉样蛋白）和细胞质（tau, a-syn， TDP）聚集体的观念？那些不涉及蛋白质聚集但至少存在但不导致神经退行性变的生物过程呢？例如，与10年前的淀粉样PET相比，小胶质PET成像还处于科学验证的早期阶段，是否已经准备好测试抗炎dmt治疗AD的靶标作用？如果是这样，当可药物靶点不是淀粉样蛋白时，淀粉样PET是否适合确定下游效应？试验学家总是会提倡更多的试验和新的方法来检测药物的益处，但生物标志物科学家应该放弃科学责任，转而支持广为人知的负面结果吗？在本期的《神经治疗学》中，一组不同的研究人员开始讨论抗淀粉样蛋白临床试验中生物标志物发展的复杂性，而不仅仅是试验富集和靶标参与。首先，Yadollahikhales和Rojas通过展示AD生物标志物在设计和解释抗淀粉样蛋白临床试验[3]中的价值，最终Leqembi®（lecanemab）成为第一个获得FDA传统批准[3]的抗淀粉样蛋白DMT。这一里程碑被一些人视为一项突破，另一些人则证实了淀粉样蛋白对阿尔茨海默病的毒性，尽管许多支持者对FDA早些时候加速批准Aduhelm®（aducanumab）持批评态度，该药物在淀粉样蛋白PET和临床衰退方面显示了类似的发现。顺便说一句，脑淀粉样蛋白负荷的相关减少（PET测量）
It has been 25 years since the US National Institutes of Health Biomarkers Definitions Working Group proposed aspirational characteristics for disease-associated biomarkers to expedite and inform therapeutics research [1]. Among neurodegenerative disorders, quantitation or visualization of peptides and aggregates involved in disease pathogenesis has been—and remains—the central tenet for biomarker development. There has been unparalleled success in the maturation and application of etiologic biomarkers for Alzheimer’s disease (AD). Whereas researchers a decade ago celebrated the consistent association between AD neuropathology with positron emission tomography (PET) or cerebrospinal fluid (CSF) biomarkers [2], we have now witnessed approval by the US Food and Drug Administration (FDA) of insoluble AD protein PET imaging, soluble CSF AD proteins, and anti-amyloid disease-modifying therapies (DMTs). These advances have not come without pitfalls or caveats, many of which are judged more through the lens of societal values than scientific impact. However, even modest triumphs in its etiologic diagnosis and treatment augment AD’s transformation from a shifty clinical syndrome to a bona fide molecular disorder. Deliberate haste in identifying and targeting amyloid appears to have yielded reasonable return on investment compared to blithe discovery efforts which often fall short on accuracy, precision, or both. Yet, amyloid is but one of many pathologic changes linking aging to AD neuropathology, and it remains controversial if the amyloid template can be applied to other aggregating proteins in AD and non-AD neurodegenerative disorders. Unlike the moderate relationship between CSF tau levels and AD neuropathology, CSF levels of a-synuclein (a-syn), tau, and TDP-43 have largely not corresponded to brain protein aggregates in Parkinson’s disease (PD) and frontotemporal lobar degeneration associated with tau (FTLD-Tau) or TDP-43 (FTLD-TDP). Should these findings reinforce the notion that one should not target extracellular (amyloid) and cytoplasmic (tau, a-syn, TDP) aggregates through the same treatment modality? What about biological processes that do not involve protein aggregation but are at least present if not contributing to neurodegeneration? For example, is microglial PET imaging—in an earlier stage of scientific validation than amyloid PET was 10 years ago—ready to test target engagement in anti-inflammatory DMTs for AD? If so, is amyloid PET appropriate to determine downstream effects when the druggable target is not amyloid? Trialists will invariably advocate for more trials and novel ways to detect drug benefits, but should biomarker scientists abdicate scientific responsibility in favor of well-publicized negative outcomes? In this issue of Neurotherapeutics, a diverse group of investigators begins to address the complexity of biomarker developments beyond trial enrichment and target engagement in anti-amyloid clinical trials. First, Yadollahikhales and Rojas set the stage by showcasing AD biomarkers’ values in designing and interpreting anti-amyloid clinical trials [3], culminating in Leqembi®(lecanemab) becoming the first anti-amyloid DMT to garner FDA’s Traditional Approval [4]. This milestone is heralded as a breakthrough by some and confirmation of amyloid toxicity in AD by others, even though many supporters were vocal critics of FDA’s earlier accelerated approval of Aduhelm®(aducanumab), which demonstrated similar findings on amyloid PET and clinical decline. Parenthetically, the correlated reduction in cerebral amyloid burden (measured on PET)