PET tau imaging in BLSA and GESTALT as an Early Marker of Alzheimer's Disease

使用Tau放射性配体AV-1451的PET成像于2016年引入BLSA研究。结合PET淀粉样蛋白成像和MRI测量，这些研究将提供阿尔茨海默病临床前阶段的信息。截至2020年3月，超过110名BLSA参与者至少进行了一次PET Tau扫描，其中一半以上进行了2次或更多次扫描。由于COVID-19，PET成像暂停至2021年5月，但由于母BLSA研究中BLSA参与者访视次数减少以及COVID-19大流行持续，PET成像已以较低速度恢复。 在过去的一年里，出版了几份手稿。 一份手稿报道了在87名中位年龄为77岁的认知正常个体中，血管风险评分与通过PET测量的淀粉样蛋白或tau负荷之间不存在关联（Bilgel et al.，2021年）。 正如预期的那样，淀粉样蛋白阳性参与者在内嗅皮层（EC）和颞下回（ITG）中有更大的tau蛋白，10年心血管风险与白色病变负荷呈正相关，这为所使用的测量方法提供了验证。 尽管有这些预测的关系，我们的数据表明，同时评估血管风险和AD神经病理学可能构成独立的途径，在认知障碍和痴呆的发展。 在最近发表的第二份手稿中，（Bilgel等人，2022），我们进行了因果中介分析，以研究淀粉样蛋白β和现有tau蛋白对tau蛋白传播和神经变性的相对贡献，这是在两项无痴呆个体的纵向研究中进行的：我们的样本来自巴尔的摩老龄化纵向研究（N = 103，年龄范围57-96）和阿尔茨海默病神经影像学倡议（N = 122，年龄范围56-92）。作为神经退行性变的代表，我们研究了脑血流量、葡萄糖代谢和局部体积。我们首先证实β淀粉样蛋白调节内嗅皮层和颞下回中tau蛋白之间的联系，颞下回是一个表现出早期tau蛋白病理学的新皮层区域。 在解释淀粉样蛋白这种促进作用的因果中介分析中，淀粉样蛋白阳性对下颞tau蛋白有显著的直接影响，并通过内嗅tau蛋白产生间接影响。 内嗅tau蛋白介导了淀粉样蛋白对颞下tau蛋白总作用的48%。较高的下颞叶tau蛋白与较低的共定位脑血流量、葡萄糖代谢和局部体积相关，而淀粉样蛋白仅通过tau蛋白对这些指标产生间接影响，表明tau蛋白是神经退行性变的主要驱动因素。 我们的研究结果表明，靶向淀粉样蛋白或内侧颞叶tau蛋白可能会减缓tau蛋白的新皮质扩散和随后的神经变性，但联合治疗可能会产生更好的结果。 与Antonio Terracciano合作，我们扩展了对人格维度与AD之间关系的调查。 在以前的研究中，我们发现，神经质得分越高，责任心得分越低，患AD的风险越大，即使是在多年前测量人格的时候。最近（Terracciano等人，2022），我们调查了神经质和尽责性与淀粉样蛋白和tau的AD生物标志物之间的关联。 在认知正常的BLSA参与者中，高神经质与PET测量的较高皮质淀粉样蛋白负荷相关（比值比1.68，95%CI 1.20-2.34），而高责任感与较低皮质淀粉样蛋白负荷相关（比值比0.61，95%CI 0.44-0.86）。在考虑了年龄、性别、教育、抑郁症状、海马体积和APOE 4后，这些相关性仍然显著。在内嗅皮层中也发现了与tau蛋白类似的联系。这些关联在12项淀粉样蛋白沉积研究和8项tau研究的荟萃分析中得到证实。 在荟萃分析中的关联被调节的认知状态，与异质性样本相比，认知正常的影响更强，这表明人格和AD病理之间的关联并不是伴随神经精神临床症状出现的现象。 这些发现表明，低神经质和高意识可能有助于抵抗淀粉样蛋白和tau神经病理学。 除了PET生物标志物的研究之外，我们正在研究接受PET淀粉样蛋白和tau蛋白研究的个体样本中AD病理学和神经变性的血浆生物标志物。 这些测定已在我们的合作者约翰霍普金斯的Abhay Moghekar博士和哥德堡大学的Zetterberg、Blennow和Ashton博士的实验室中进行，分析正在进行中。

PET imaging with the Tau radioligand AV-1451 was introduced into the BLSA study in 2016. In combination with PET amyloid imaging and MRI measures, these studies will provide information on the preclinical stages of Alzheimer's Disease. Through March, 2020, more than 110 BLSA participants had at least one PET Tau scan, and of these, more than half had 2 or more scans. Due to COVID-19, PET imaging was suspended through May 2021 but has resumed at a reduced rate due to the diminished numbers of BLSA participant visits in the parent BLSA study and the continuing COVID19 pandemic. Several manuscripts have been published over the last year. One manuscript reported the absence of associations between vascular risk scores and amyloid or tau burden measured by PET in 87 cognitively normal individuals with median age of 77 years (Bilgel et al., 2021). As expected, amyloid positive participants had greater tau in the entorhinal cortex (EC) and inferior temporal gyrus (ITG), and 10-year cardiovascular risk was positively correlated with white matter lesion burden, providing a validation of the measures used. Despite these predicted relationships, our data suggest that concurrently assessed vascular risk and AD neuropathology may constitute independent pathways in the development of cognitive impairment and dementia. In a second recently published manuscript (Bilgel et al, 2022), we conducted causal mediation analyses to investigate the relative contributions of amyloid-beta and existing tau to tau propagation and neurodegeneration in two longitudinal studies of individuals without dementia: our sample from the Baltimore Longitudinal Study of Aging (N = 103, age range 57-96) and the Alzheimer's Disease Neuroimaging Initiative (N = 122, age range 56-92). As proxies of neurodegeneration, we investigated cerebral blood flow, glucose metabolism, and regional volume. We first confirmed that amyloid-beta moderates the association between tau in the entorhinal cortex and in the inferior temporal gyrus, a neocortical region exhibiting early tau pathology. In causal mediation analyses accounting for this facilitating effect of amyloid, amyloid positivity had a significant direct effect on inferior temporal tau as well as an indirect effect via entorhinal tau. Entorhinal tau mediated up to 48% of the total effect of amyloid on inferior temporal tau. Higher inferior temporal tau was associated with lower colocalized cerebral blood flow, glucose metabolism, and regional volume, whereas amyloid had only an indirect effect on these measures via tau, suggesting tau is the primary driver of neurodegeneration. Our findings suggest targeting amyloid or medial temporal lobe tau might slow neocortical spread of tau and subsequent neurodegeneration, but a combination therapy may yield better outcomes. In collaboration with Antonio Terracciano, we extended our investigation of the relationship between personality dimensions and AD. In previous studies, we had found that higher scores on Neuroticism and lower scores on Conscientiousness were associated with greater risk for AD, even when personality was measured many years earlier. More recently (Terracciano et al., 2022), we investigated the association between Neuroticism and Conscientiousness and AD biomarkers of amyloid and tau. Among cognitively normal BLSA participants, Higher Neuroticism was associated with higher cortical amyloid burden measured by PET (odds ratio 1.68, 95% CI 1.20-2.34), and higher Conscientiousness was associated with lower cortical amyloid burden (odds ratio 0.61, 95% CI 0.44-0.86). These associations remained significant after accounting for age, sex, education, depressive symptoms, hippocampal volume, and APOE 4. Similar associations were found with tau in the entorhinal cortex. These associations were confirmed in meta-analyses of 12 studies for amyloid deposition and 8 studies for tau. The associations in the meta-analysis were moderated by cognitive status, with stronger effects in cognitively normal compared with heterogeneous samples, suggesting that the associations between personality and AD pathologies are not phenomena that emerge with neuropsychiatric clinical symptoms. These findings suggest that low Neuroticism and high Consciousness may contribute to resistance against amyloid and tau neuropathology. In addition to the study of PET biomarkers, we are investigating plasma biomarkers of AD pathology and neurodegeneration in the sample of individuals who have underg2one PET amyloid and tau studies. These assays have been performed in the laboratories of our collaborators, Dr. Abhay Moghekar at Johns Hopkins, and Drs. Drs. Zetterberg, Blennow and Ashton at Gothenburg University, and analyses are ongoing.