Department of Biomedical and Neuromotor Sciences University of Bologna Bologna 40123 Italy.
IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna 40139 Italy.
Ann Clin Transl Neurol. 2018 Dec 14;6(2):263-273. doi: 10.1002/acn3.697. eCollection 2019 Feb.
Despite the critical importance of pathologically confirmed samples for biomarker validation, only a few studies have correlated CSF A42 values in vivo with postmortem Alzheimer's disease (AD) pathology, while none evaluated the CSF A42/A40 ratio. We compared CSF A42 and A42/A40 ratio as biomarkers predicting AD neuropathological changes in patients with a short interval between lumbar puncture and death.
We measured CSF A40 and A42 and assessed AD pathology in 211 subjects with rapidly progressive dementia (RPD) and a definite postmortem diagnosis of Creutzfeldt-Jakob disease ( = 159), AD ( = 12), dementia with Lewy bodies (DLB, = 4), AD/DLB mixed pathologies ( = 5), and various other pathologies ( = 31).
The score reflecting the severity of A pathology showed a better correlation with ln(A42/A40) ( = 0.506, = -0.713, < 0.001) than with ln(A42) ( = 0.206, = -0.458, < 0.001), which was confirmed after adjusting for covariates. A42/A40 ratio showed significantly higher accuracy than A42 in the distinction between cases with or without AD pathology (AUC 0.818 ± 0.028 vs. 0.643 ± 0.039), especially in patients with A42 levels ≤495 pg/mL (AUC 0.888 ± 0.032 vs. 0.518 ± 0.064). Using a cut-off value of 0.810, the analysis of A42/A40 ratio yielded 87.0% sensitivity, 88.2% specificity in the distinction between cases with an intermediate-high level of AD pathology and those with low level or no AD pathology.
The present data support the use of CSF A42/A40 ratio as a biomarker of AD pathophysiology and noninvasive screener for A pathology burden, and its introduction in the research diagnostic criteria for AD.
尽管病理性确认样本对于生物标志物验证至关重要，但仅有少数研究将活体内 CSF A42 值与阿尔茨海默病（AD）的死后病理学相关联，而没有研究评估 CSF A42/A40 比值。我们比较了 CSF A42 和 A42/A40 比值作为生物标志物，以预测腰椎穿刺与死亡之间间隔较短的患者的 AD 神经病理学变化。
我们测量了 211 例快速进行性痴呆（RPD）患者的 CSF A40 和 A42，并评估了 Creutzfeldt-Jakob 病（CJD，n=159）、AD（n=12）、路易体痴呆（DLB，n=4）、AD/DLB 混合病理学（n=5）和其他各种病理学（n=31）的 AD 病理学。
反映 A 病理严重程度的评分与 ln（A42/A40）的相关性更好（r=0.506，P<0.001），而与 ln（A42）的相关性更差（r=0.206，P<0.001），这在调整协变量后得到了证实。A42/A40 比值在区分有无 AD 病理学病例方面的准确性明显高于 A42（AUC 0.818±0.028 与 0.643±0.039），尤其是在 A42 水平≤495pg/mL 的患者中（AUC 0.888±0.032 与 0.518±0.064）。使用 0.810 的截断值，A42/A40 比值分析在区分 AD 病理学中高水平和低水平或无 AD 病理学病例时，灵敏度为 87.0%，特异性为 88.2%。
本研究数据支持 CSF A42/A40 比值作为 AD 病理生理学的生物标志物和 AD 病理负担的非侵入性筛查，并支持其纳入 AD 的研究诊断标准。
