背景:脑脊液(CSF)p-tau235是阿尔茨海默病(AD)高度特异性的新型生物标志物。然而,CSFp-tau235仅在特征明确的研究队列中进行了研究,这不能充分反映在临床环境中发现的患者景观。因此,在这项多中心研究中,我们调查了CSFp-tau235在临床环境中检测有症状AD的表现,并将其与CSFp-tau181,p-tau217和p-tau231进行了比较.
方法:在两个独立的记忆临床队列中使用内部单分子阵列(Simoa)测定法测量CSFp-tau235:巴黎队列(LariboisièreFernand-WidalUniversityHospitalParis,法国;n=212)和BIODEGMAR队列(医院德尔马,巴塞罗那,西班牙;n=175)。根据综合征诊断对患者进行分类(认知未受损[CU],轻度认知障碍[MCI]或痴呆)及其生物学诊断(淀粉样β[Aβ]或Aβ-)。两个队列包括详细的认知评估和CSF生物标志物测量(临床验证的核心AD生物标志物[LumipulseCSFAβ1-42/40比率,p-tau181和t-tau]和内部开发的SimoaCSFp-tau181,p-tau217和p-tau231)。
结果:无论临床诊断如何,高CSFp-tau235水平与CSF淀粉样变性强相关,与所有其他Aβ-组相比,MCIAβ+和痴呆Aβ+显著增加(巴黎队列:全部P<0.0001;BIODEGMAR队列:全部P<0.05)。与A-T和A+T-组相比,A+T+组的CSFp-tau235明显升高(P均为0.0001)。此外,CSFp-tau235在有症状的情况下(AUC=0.86至0.96)和区分AT组(AUC=0.79至0.98)显示出较高的诊断准确性。总的来说,CSFp-tau235在区分各种情况下的CSF淀粉样变性时,表现出与CSFp-tau181和CSFp-tau231相似的表现。但低于CSFp-tau217.最后,CSFp-tau235与两个队列中的整体认知和记忆域相关。
结论:在两个独立的记忆临床队列中,CSFp-tau235随着CSF淀粉样变性的存在而增加。CSFp-tau235在MCI和痴呆患者中准确识别AD。总的来说,CSFp-tau235的诊断性能与其他CSFp-tau测量相当,表明其在临床环境中支持基于生物标志物的AD诊断的适用性。
Cerebrospinal fluid (CSF) p-tau235 is a novel biomarker highly specific of Alzheimer\'s disease (AD). However, CSF p-tau235 has only been studied in well-characterized research cohorts, which do not fully reflect the patient landscape found in clinical settings. Therefore, in this multicentre study, we investigated the performance of CSF p-tau235 to detect symptomatic AD in clinical settings and compared it with CSF p-tau181, p-tau217 and p-tau231.
CSF p-tau235 was measured using an in-house single molecule array (Simoa) assay in two independent memory clinic cohorts: Paris cohort (Lariboisière Fernand-Widal University Hospital Paris, France; n=212) and BIODEGMAR cohort (Hospital del Mar, Barcelona, Spain; n=175). Patients were classified by the syndromic diagnosis (cognitively unimpaired [CU], mild cognitive impairment [MCI] or dementia) and their biological diagnosis (amyloid-beta [Aβ]+ or Aβ -). Both cohorts included detailed cognitive assessments and CSF biomarker measurements (clinically validated core AD biomarkers [Lumipulse CSF Aβ1-42/40 ratio, p-tau181 and t-tau] and in-house developed Simoa CSF p-tau181, p-tau217 and p-tau231).
High CSF p-tau235 levels were strongly associated with CSF amyloidosis regardless of the clinical diagnosis, being significantly increased in MCI Aβ+ and dementia Aβ+ when compared with all other Aβ- groups (Paris cohort: P ˂0.0001 for all; BIODEGMAR cohort: P ˂0.05 for all). CSF p-tau235 was pronouncedly increased in the A+T+ profile group compared with A-T- and A+T- groups (P ˂0.0001 for all). Moreover, CSF p-tau235 demonstrated high diagnostic accuracies identifying CSF amyloidosis in symptomatic cases (AUCs=0.86 to 0.96) and discriminating AT groups (AUCs=0.79 to 0.98). Overall, CSF p-tau235 showed similar performances to CSF p-tau181 and CSF p-tau231 when discriminating CSF amyloidosis in various scenarios, but lower than CSF p-tau217. Finally, CSF p-tau235 associated with global cognition and memory domain in both cohorts.
CSF p-tau235 was increased with the presence of CSF amyloidosis in two independent memory clinic cohorts. CSF p-tau235 accurately identified AD in both MCI and dementia patients. Overall, the diagnostic performance of CSF p-tau235 was comparable to that of other CSF p-tau measurements, indicating its suitability to support a biomarker-based AD diagnosis in clinical settings.