Project 1 - Biomarkers of Neurovascular Function

P01和项目1的重点仍然是“神经血管假说”，认为在神经血管的变化， 脑血管系统有助于认知下降、痴呆和AD。我们建议在 APOE 4携带者（ε3/ε4; ε4/ε4）具有AD的高遗传风险，并随着年龄的加速而发展 相对于APOE 3纯合子（ε3/ε3）的脑血管变化，AD风险较低，发展较慢 脑血管改变具体来说，我们假设脑血管的变化和崩溃， 血脑屏障（BBB）先于并预测临床前认知衰退和临床进展， APOE 4携带者中认知未受损（CU）至轻度认知障碍（MCI），以及MCI至痴呆> APOE 3纯合子独立于Aβ和tau AD生物标志物变化，并且在神经变性之前。到 为了验证这一点，我们将纵向跟踪402名APOE 4和465名APOE 3参与者（年龄45-90岁）， CU（75%）和MCI（25%）。我们将使用：用途：1）先进的BBB和NVU细胞的分子生物标志物评估- 在CSF和血浆中同时测量Aβ和tau生物标志物的特异性生物标志物; 2）高级MRI 评估与CBF变化相关的局部BBB渗透性; 3）使用AT（N）的临床前AD分期 生物标志物系统;和4）通过UDS 3.0 CDR和不同的神经心理学测试的认知下降 认知领域三个目标将在APOE 4携带者和APOE 3纯合子中检验我们的假设：1） 通过与系列Aβ和tau AD相关的系列CSF分析，纵向评价BBB破坏的生物标志物 生物标志物（CSF、PET）变化和认知功能下降（AIM 1）; 2）通过连续DCE-MRI测定的BBB通透性 与BBB分解的系列CSF生物标志物、Aβ和tau AD生物标志物（CSF、PET）相关的测量 变化和认知下降（AIM 2）; 3）通过与连续DCE-MRI测量相关的连续DCE-MRI测量进行的BBB破坏 CBF pCASL-MRI测量、Aβ和tau AD生物标志物（CSF、PET）变化和认知下降（AIM 3）。 我们希望表明，血脑屏障/血管功能障碍在临床前和早期认知功能下降中起着重要作用， APOE 4携带者> APOE 3纯合子，并且生物流体中BBB分解的生物标志物，以及BBB和CBF MRI测量将作为认知障碍、痴呆和早期痴呆的可靠的新的预后生物标志物。 AD.这项工作的结果可能会导致新的思路发病机制，治疗和早期 预防认知障碍、痴呆和AD，我们仍然没有有效的治疗方法。

The focus of P01 and Project 1 remains on the ‘neurovascular hypothesis’, which holds that changes in the cerebrovascular system contribute to cognitive decline, dementia and AD. We propose to test the hypothesis in APOE4 carriers (ε3/ε4; ε4/ε4) that are at high genetic risk for AD and develop with age accelerated cerebrovascular changes relative to APOE3 homozygotes (ε3/ε3) that are at lower risk for AD and develop slower cerebrovascular changes. Specifically, we hypothesize that cerebrovascular changes and breakdown in the blood-brain barrier (BBB) precede and predict preclinical cognitive decline and clinical progression from cognitively unimpaired (CU) to mild cognitive impairment (MCI), and MCI to dementia, in APOE4 carriers > APOE3 homozygotes independently of Aβ and tau AD biomarker changes, and prior to neurodegeneration. To test this, we will follow longitudinally 402 APOE4 and 465 APOE3 participants (ages 45-90), initially enrolled as CU (75%) and MCI (25%). We will use: 1) Advanced molecular biomarker assessment of BBB and NVU cell- specific biomarkers measured simultaneously in CSF and plasma with Aβ and tau biomarkers; 2) Advanced MRI assessment of regional BBB permeability in relation to CBF changes; 3) Preclinical AD staging using AT(N) biomarkers system; and 4) Cognitive decline by UDS 3.0 CDR and neuropsychological tests across different cognitive domains. Three aims will test our hypothesis in APOE4 carriers and APOE3 homozygotes to 1) Evaluate longitudinally biomarkers of BBB breakdown by serial CSF analysis in relation to serial Aβ and tau AD biomarker (CSF, PET) changes and cognitive decline (AIM 1); 2) BBB permeability by serial DCE-MRI measurements in relation to serial CSF biomarkers of BBB breakdown, Aβ and tau AD biomarker (CSF, PET) changes and cognitive decline (AIM 2); 3) BBB breakdown by serial DCE-MRI measurements in relation to serial CBF pCASL-MRI measurements, Aβ and tau AD biomarker (CSF, PET) changes and cognitive decline (AIM 3). We expect to show that BBB/vascular dysfunction plays a major role in preclinical and early cognitive decline in APOE4 carriers > APOE3 homozygotes, and that biomarkers of BBB breakdown in biofluids, and BBB and CBF MRI measures will serve as reliable new prognostic biomarkers for cognitive impairment, dementia and early AD. The results of this work may lead to new ways of thinking about pathogenesis, treatment and early prevention of cognitive impairment, dementia and AD for which we still do not have effective therapies.