Butler Hospital Memory & Aging Program, 345 Blackstone Boulevard, Providence, RI, 02906, USA.
Department of Psychiatry and Human Behavior, Brown University, Providence, RI, USA.
Alzheimers Res Ther. 2024 Jul 6;16(1):154. doi: 10.1186/s13195-024-01521-9.
With the approval of disease-modifying treatments (DMTs) for early Alzheimer's disease (AD), there is an increased need for efficient and non-invasive detection methods for cerebral amyloid-β (Aβ) pathology. Current methods, including positron emission tomography (PET) and cerebrospinal fluid (CSF) analysis, are costly and invasive methods that may limit access to new treatments. Plasma tau phosphorylated at threonine-217 (P-tau217) presents a promising alternative, yet optimal cutoffs for treatment eligibility with DMTs like aducanumab require further investigation. This study evaluates the efficacy of one- and two-cutoff strategies for determining DMT eligibility at the Butler Hospital Memory & Aging Program (MAP).
In this retrospective, cross-sectional diagnostic cohort study, we first developed P-tau217 cutoffs using site-specific and BioFINDER-2 training data, which were then tested in potential DMT candidates from Butler MAP (total n = 150). ROC analysis was used to calculate the area under the curve (AUC) and accuracy of P-tau217 interpretation strategies, using Aβ-PET/CSF testing as the standard of truth.
Potential DMT candidates at Butler MAP (n = 50), primarily diagnosed with mild cognitive impairment (n = 29 [58%]) or mild dementia (21 [42%]), were predominantly Aβ-positive (38 [76%]), and half (25 [50%]) were subsequently treated with aducanumab. Elevated P-tau217 predicted cerebral Aβ positivity in potential DMT candidates (AUC = 0.97 [0.92-1]), with diagnostic accuracy ranging from 0.88 (0.76-0.95, p = 0.028) to 0.96 (0.86-1, p < .001). When using site-specific cutoffs, a subset of DMT candidates (10%) exhibited borderline P-tau217 (between 0.273 and 0.399 pg/mL) that would have potentially required confirmatory testing.
This study, which included participants treated with aducanumab, confirms the utility of one- and two-cutoff strategies for interpreting plasma P-tau217 in assessing DMT eligibility. Using P-tau217 could potentially replace more invasive diagnostic methods, and all aducanumab-treated participants would have been deemed eligible based on P-tau217. However, false positives remain a concern, particularly when applying externally derived cutoffs that exhibited lower specificity which could have led to inappropriate treatment of Aβ-negative participants. Future research should focus on prospective validation of P-tau217 cutoffs to enhance their generalizability and inform standardized treatment decision-making across diverse populations.
随着针对早期阿尔茨海默病（AD）的疾病修饰疗法（DMT）的批准，人们对脑淀粉样蛋白-β（Aβ）病理学的有效且非侵入性检测方法的需求日益增加。目前的方法，包括正电子发射断层扫描（PET）和脑脊液（CSF）分析，都是昂贵且具有侵入性的方法，可能会限制新疗法的应用。磷酸化的 tau 蛋白在苏氨酸-217 处（P-tau217）表现出很有前景的替代方法，然而，像 aducanumab 这样的 DMT 的治疗资格的最佳截止值仍需要进一步研究。本研究评估了在巴特勒医院记忆与衰老计划（MAP）中使用单截止值和双截止值策略来确定 DMT 资格的效果。
在这项回顾性、横断面诊断队列研究中，我们首先使用特定于地点的和 BioFINDER-2 训练数据开发了 P-tau217 的截止值，然后在巴特勒 MAP 的潜在 DMT 候选者（总共 150 名）中进行了测试。使用 Aβ-PET/CSF 测试作为金标准，通过 ROC 分析计算 P-tau217 解释策略的曲线下面积（AUC）和准确性。
巴特勒 MAP 的潜在 DMT 候选者（n=50），主要被诊断为轻度认知障碍（n=29 [58%]）或轻度痴呆（n=21 [42%]），主要为 Aβ 阳性（n=38 [76%]），其中一半（n=25 [50%]）随后接受了 aducanumab 治疗。升高的 P-tau217 预测了潜在 DMT 候选者的脑 Aβ 阳性（AUC=0.97 [0.92-1]），诊断准确性范围为 0.88（0.76-0.95，p=0.028）至 0.96（0.86-1，p<0.001）。当使用特定于地点的截止值时，一部分 DMT 候选者（10%）的 P-tau217 表现为边缘值（在 0.273 到 0.399 pg/mL 之间），这可能需要进行确认性测试。
这项包括接受 aducanumab 治疗的参与者的研究证实了单截止值和双截止值策略在评估 DMT 资格方面解释血浆 P-tau217 的有效性。使用 P-tau217 可能会替代更具侵入性的诊断方法，并且所有接受 aducanumab 治疗的参与者都将被认为符合 P-tau217 的标准。然而，假阳性仍然是一个问题，特别是当应用外部推导的截止值时，其特异性较低，这可能导致对 Aβ 阴性参与者的不适当治疗。未来的研究应集中在 P-tau217 截止值的前瞻性验证上，以提高其普遍性，并为不同人群的标准化治疗决策提供信息。
