Neuroimaging Predictors of Cognitive Decline, Impairment, and Resilience

工作总结：与年龄相关的认知和记忆变化的神经解剖学和神经生理学基础仍然不清楚，因为没有痴呆症的个体的纵向大脑变化的研究数量有限。我们正在对来自巴尔的摩老龄化纵向研究（BLSA）的参与者进行系列磁共振成像（MRI），包括血管变化的测量、正电子发射断层扫描（PET）和神经心理学评估，以调查记忆变化和认知障碍的神经生物学基础。这些评估使我们能够检查大脑结构和功能的变化，这些变化可能是认知变化和障碍的早期预测因素，包括阿尔茨海默病（AD）。我们正在继续对老年参与者进行纵向测试，并对新参与者进行评估，包括对55岁以下参与者进行MRI和同步神经心理学评估。 对于55岁及以上的个体，我们目前也进行CBF的单次PET测量，然后使用11-C-匹兹堡化合物B（Pi B）进行PET扫描以测量体内淀粉样蛋白分布。我们在过去一年中取得的进展包括继续获得新的神经影像学评估以及继续分析现有数据和方法开发。 大约一半的神经影像学研究参与者参加了BLSA尸检计划，尸检和成像结果的整合是一个活跃的调查领域，以更好地了解促进淀粉样蛋白病理学患者认知恢复力的因素，但没有表现出记忆障碍。 此外，我们正在使用神经成像工具来研究认知和大脑变化的调节剂，包括大脑老化的性别差异，遗传风险因素以及性类固醇和其他激素的影响。了解这些大脑行为关联，并早期检测预测认知能力下降和障碍的大脑加速变化，对于确定可能从新干预措施中受益的个体至关重要。 在过去的一年里，我们发表了一些关于这项研究的论文。 与其他中心和尸检研究的成像结果一致，我们发现大约30%的认知正常的老年人大脑中有可检测到的淀粉样蛋白水平。我们的PiB研究表明，认知正常个体中较高的PiB水平与精神状态和记忆随时间的更大下降相关（Resnick et al，2010），但PiB与正常个体中的局部组织损失无显著相关性（Drivel et al，2011）。 这些研究还揭示了在初始PiB评估时具有较高PiB保留的个体中PiB保留的纵向增加（Sojkova et al，2011），以及根据用于AD病理诊断的CERAD分类，体内淀粉样蛋白成像模式与淀粉样蛋白斑块的病理评级之间的一致性和不一致性（Sojkova et al，2010）。 我们的成像神经病理学分析强调了使用标准神经病理学诊断进行PiB尸检验证的困难，这是由于在标准CERAD评估下检查的区域和在PiB成像上显示最早淀粉样蛋白沉积的脑区域之间的差异。我们正在使用PiB结合的空间模式（以及MRI组织损失和病变）来指导更详细的尸检分析。 此外，我们还研究了clusterin和其他血浆蛋白浓度和遗传风险与PiB水平和模式的关系。 基线神经影像学评估时血浆中较高的丛生蛋白浓度与10年后较高的内侧颞叶PiB保留相关（Thambisetty et al，2010）。 此外，我们将蛋白质组学与体内淀粉样蛋白成像相结合，以鉴定一组18个2DGE血浆蛋白斑点，这些斑点可区分具有高和低脑A的个体（Thambisetty et al，2010）。质谱鉴定了这些蛋白质，其中许多蛋白质在A清除中具有确定的作用，包括来自载脂蛋白E（ApoE）的强信号。血浆ApoE浓度与内侧颞叶的A负荷增加相关，在海马和内嗅皮质中最明显。 APOE 4携带者在几个脑区的A水平也高于4个非携带者。这些结果表明，外周浓度的载脂蛋白E蛋白和载脂蛋白E基因型相关的早期神经病理学变化的大脑区域，即使在非痴呆老年人的病理学易受AD。 来自该项目的数据也继续用于重要的方法学发展，以增强纵向神经成像数据的分析，包括描述MRI上颅骨剥离的新方法的论文（Carass等人，2011），成像数据的聚类分析，用于检测反映受试者的MR图像与正常MR图像的偏差的基于聚类的病理测量。（认知稳定）状态（Filipovych等人，2011），以及生物参数映射的扩展，以包括在一般线性模型的应用的神经成像背景下的稳健回归和稳健推断（Xue等人，2011）。

Summary of work: The neuroanatomic and neurophysiologic underpinnings of age-associated cognitive and memory change remain unclear, as there are a limited number of studies of longitudinal brain changes in individuals without dementia. We are performing serial magnetic resonance imaging (MRI), including measures of vascular changes, positron emission tomography (PET), and neuropsychological assessments in participants from the Baltimore Longitudinal Study of Aging (BLSA) to investigate the neurobiological basis of memory change and cognitive impairment. These evaluations allow us to examine changes in brain structure and function which may be early predictors of cognitive change and impairment, including Alzheimer's disease (AD). We are continuing longitudinal testing of older participants and evaluating new participants, including MRI and concurrent neuropsychological assessments of participants less than 55 years old. For individuals aged 55 and older, we also currently perform a single PET measurement of CBF, followed by a PET scan using 11-C-Pittsburgh Compound B (PiB) to measure in vivo amyloid distribution. Our progress over the last year includes continued acquisition of new neuroimaging assessments as well as continued analysis of existing data and methods development. Approximately half of the neuroimaging study participants are enrolled in the BLSA autopsy program, and the integration of autopsy and imaging findings is an active area of investigation to gain a better understanding of factors that promote cognitive resilience in individuals who have amyloid pathology but do not show memory impairment. In addition, we are using neuroimaging tools to investigate modulators of cognitive and brain changes, including sex differences in brain aging, genetic risk factors, and the effects of sex steroid and other hormones. An understanding of these brain-behavior associations and early detection of accelerated brain changes that predict cognitive decline and impairment will be critical in identifying individuals likely to benefit from new interventions. Over the last year, we have published a number of papers from this study. Consistent with imaging findings at other centers and autopsy studies, we find that about 30 percent of cognitively normal older adults have detectable levels of amyloid in the brain. Our PiB studies have demonstrated that higher PiB levels in cognitively normal individuals are associated with greater decline over time in mental status and memory (Resnick et al, 2010) but PiB was not significantly associated with regional tissue loss in normal individuals (Driscoll et al, 2011). These studies also have revealed longitudinal increases in PiB retention in individuals with higher PiB retention at initial PiB assessment (Sojkova et al, 2011) and the concordance and discordance between in vivo amyloid imaging patterns and pathological ratings of amyloid plaques according to the CERAD classification for pathological diagnosis of AD (Sojkova et al, 2010). Our imaging-neuropathology analyses have highlighted difficulties in using standard neuropathological diagnosis for autopsy validation of PiB due to differences in regions examined under the standard CERAD assessment and the brain regions showing the earliest amyloid deposition on PiB imaging. We are using the spatial patterns of PiB binding (and MRI tissue loss and lesions) to guide more detailed autopsy analyses. In addition, we have investigated clusterin and other plasma protein concentrations and genetic risk in relation to PiB levels and patterns. Higher clusterin concentration in plasma at baseline neuroimaging assessment was associated with higher medial temporal PiB retention more than 10 years later (Thambisetty et al, 2010). In addition, we combined proteomics with in in vivo amyloid imaging to identify a panel of 18 2DGE plasma protein spots that discriminated between individuals with high and low brain Aβ (Thambisetty et al, 2010). Mass spectrometry identified these proteins, many of which have established roles in Aβ clearance, including a strong signal from apolipoprotein-E (ApoE). Plasma ApoE concentration was associated with increased Aβ burden in the medial temporal lobe, most pronounced in the hippocampus and entorhinal cortex. APOE ε4 carriers also showed greater Aβ levels in several brain regions relative to ε4 non-carriers. These results suggest that both peripheral concentration of ApoE protein and APOE genotype are related to early neuropathological changes in brain regions vulnerable to AD pathology even in the non-demented elderly. The data from this project also continue to be used for important methodological developments to enhance analysis of longitudinal neuroimaging data, including papers describing new approaches for skull-stripping on MRI (Carass et al., 2011), cluster analysis of imaging data for detection of a cluster-based measure of pathology that reflects the deviation of a subject's MR image from a normal (i.e. cognitively stable) state (Filipovych et al, 2011), and an extension of Biological Parametric Mapping to include robust regression and robust inference in the neuroimaging context of application of the general linear model (Xue et al, 2011).