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Abstract：
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.
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.
摘要：
背景：随着早期阿尔茨海默病（AD）的疾病修饰治疗（DMT）的批准，对脑淀粉样β(Aβ)病理的有效和非侵入性检测方法的需求增加。目前的方法，包括正电子发射断层扫描（PET）和脑脊液（CSF）分析，是昂贵且侵入性的方法，可能会限制获得新的治疗方法。在苏氨酸-217（P-tau217）磷酸化的血浆tau提出了一个有希望的替代方案，然而,使用aducanumab等DMT的最佳治疗资格还需要进一步研究.这项研究评估了在巴特勒医院记忆与衰老计划（MAP）中确定DMT资格的一截止和两截止策略的有效性。
方法：在本回顾性研究中，横断面诊断队列研究，我们首先使用特定站点和BioFINDER-2训练数据开发了P-tau217截止值，然后在来自ButlerMAP的潜在DMT候选物中进行测试（总n=150）。ROC分析用于计算曲线下面积（AUC）和P-tau217解释策略的准确性，使用Aβ-PET/CSF测试作为真理的标准。
结果：巴特勒MAP的潜在DMT候选者（n=50），主要诊断为轻度认知障碍（n=29[58%]）或轻度痴呆（21[42%]），主要为Aβ阳性（38[76%]），一半（25[50%]）随后接受了阿杜卡单抗治疗。P-tau217在潜在的DMT候选物中预测脑Aβ阳性（AUC=0.97[0.92-1]），诊断准确性范围从0.88（0.76-0.95，p=0.028）到0.96（0.86-1，p<.001）。使用特定于站点的截止值时，一部分DMT候选物(10%)显示P-tau217临界线(0.273~0.399pg/mL),可能需要进行验证性测试.
结论：这项研究，其中包括接受aducanumab治疗的参与者，确认了一截止和两截止策略在评估DMT合格性时解释血浆P-tau217的实用性。使用P-tau217可能会取代更具侵入性的诊断方法，根据P-tau217,所有接受aducanumab治疗的参与者均被视为符合条件.然而,假阳性仍然是一个令人担忧的问题，特别是当应用外部来源的显示较低特异性的截止值时，这可能导致对Aβ阴性参与者的不适当治疗。未来的研究应该集中在P-tau217截止值的前瞻性验证上，以增强其普遍性，并为不同人群的标准化治疗决策提供信息。
方法：在本回顾性研究中，横断面诊断队列研究，我们首先使用特定站点和BioFINDER-2训练数据开发了P-tau217截止值，然后在来自ButlerMAP的潜在DMT候选物中进行测试（总n=150）。ROC分析用于计算曲线下面积（AUC）和P-tau217解释策略的准确性，使用Aβ-PET/CSF测试作为真理的标准。
结果：巴特勒MAP的潜在DMT候选者（n=50），主要诊断为轻度认知障碍（n=29[58%]）或轻度痴呆（21[42%]），主要为Aβ阳性（38[76%]），一半（25[50%]）随后接受了阿杜卡单抗治疗。P-tau217在潜在的DMT候选物中预测脑Aβ阳性（AUC=0.97[0.92-1]），诊断准确性范围从0.88（0.76-0.95，p=0.028）到0.96（0.86-1，p<.001）。使用特定于站点的截止值时，一部分DMT候选物(10%)显示P-tau217临界线(0.273~0.399pg/mL),可能需要进行验证性测试.
结论：这项研究，其中包括接受aducanumab治疗的参与者，确认了一截止和两截止策略在评估DMT合格性时解释血浆P-tau217的实用性。使用P-tau217可能会取代更具侵入性的诊断方法，根据P-tau217,所有接受aducanumab治疗的参与者均被视为符合条件.然而,假阳性仍然是一个令人担忧的问题，特别是当应用外部来源的显示较低特异性的截止值时，这可能导致对Aβ阴性参与者的不适当治疗。未来的研究应该集中在P-tau217截止值的前瞻性验证上，以增强其普遍性，并为不同人群的标准化治疗决策提供信息。
