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，因为对无痴呆个体的纵向大脑变化的研究数量有限。我们正在对巴尔的摩衰老纵向研究（BLSA）的参与者进行一系列磁共振成像（MRI），包括血管变化测量、正电子发射断层扫描（PET）和神经心理学评估，以研究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损害的早期预测因素，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，包括对年龄小于55岁的参与者进行MRI和同步神经心理学评估。对于55岁及以上的个体，我们目前也对CBF进行单次PET测量，然后使用11- c -匹兹堡化合物B （PiB）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，以及对现有数据和方法的持续分析。大约一半的神经影像学研究参与者参加了BLSA的尸检项目，并且将尸检和影像学结果结合起来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但没有表现出记忆障碍的个体的认知恢复能力的因素。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，包括大脑衰老中的性别差异、遗传风险因素、性类固醇和其他激素的影响。了解这些脑-行为关联和早期发现预测认知能力下降和损伤的加速大脑变化，对于识别可能从新的干预措施中受益的个体至关重要。

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).