Neuroimaging Predictors Of Cognitive Change And Response To Therapy

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不清楚，因为关于非痴呆症患者的纵向脑变化的研究数量有限。我们正在对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)、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，这可能是认知变化和损伤的早期预测因素，包括阿尔茨海默病(AD)。了解这些关联并及早发现大脑变化，对于确定可能从新干预措施中受益的个人至关重要。自2005年以来，我们还获得了11-C-PIB脑内淀粉样蛋白分布的PET成像研究，以加强对临床前AD的识别。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因素，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。 我们继续对巴尔的摩老龄化纵向研究的神经成像研究参与者进行系列MRI和PET扫描。我们最初的纵向MRI研究显示，即使在健康的老年人中，灰质和白质组织的纵向丢失在四年的时间间隔中也是显著的(Resnick等人，J NeuroScience 2003)。最近，我们证实了这些发现，并对其进行了更长时间(长达9年)的随访(Driscoll等人，《神经学》，2009年)。此外，我们还证明，在轻度认知障碍(MCI)患者中，除总体脑体积外，许多大脑区域，包括海马体和眼眶额区，都显示出加速的组织丢失。我们使用支持向量机算法来开发分类器，用于预测个人的诊断状态。我们在与重要人口统计学特征匹配的个体样本中发现了一个异常网络，该网络有助于最大限度地区分正常和MCI患者的MRI扫描(Fan等人，NeuroImage2008)。然后，我们将这种方法应用于阿尔茨海默病神经成像倡议(ADNI)的AD患者和对照组，并使用基于该样本的分类器来计算每个BLSA参与者的所有MRI扫描的早期AD(Sare-AD)分数的异常空间模式。我们证明了较高的Spare-AD异常得分与较低的言语记忆表现相关(Davatzikos等人，Brain 2009)，并且异常得分随着年龄和认知障碍的增加而增加。 使用11-C-PIB PET扫描数据，我们证实了其他中心的经验，即20-30%的认知正常老年人有PIB阳性扫描，即大脑淀粉样蛋白沉积。此外，我们还调查了前几年PIB滞留是否与rCBF纵向变化有关(Sojkova等人，2008年)。通过将参考组织模型与测量的时间活动曲线相匹配来估计感兴趣区域的PIB分布体积比(周等人，NeuroImage，2007)。使用平均皮质DVR将参与者分为高PIB保留组和低PIB保留组。与高PIB相关的两个区域的rCBF纵向减少和纵向增加均较大。虽然纵向下降可能反映了高PIB组神经元功能的更大程度的下降，但在那些淀粉样蛋白负荷更高的人中也观察到了更大的rCBF纵向增加，这可能代表着对这些区域神经元功能的代偿性尝试。 大约一半的神经成像研究参与者参加了BLSA尸检计划，尸检和成像结果的整合是一个活跃的研究领域(例如，Iacono等人，2008年)。BLSA研究表明，尸检时患有AD病理但没有生前认知障碍(无症状AD)的人，其前扣带回、后扣带回和海马体的核和核仁较大，表明存在代偿或炎症过程。正在进行的研究调查神经成像发现的细胞基础，包括区域体积丢失，以试图更好地定义加速认知损害的特征以及那些支持维持认知健康的特征。

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), 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). An understanding of these associations and early detection of brain changes will be critical in identifying individuals likely to benefit from new interventions. Since 2005, we also have acquired 11-C-PIB PET imaging studies of amyloid distribution in the brain to enhance the identification of preclinical AD. 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. We continue to perform serial MRI and PET scans for neuroimaging study participants of the Baltimore Longitudinal Study of Aging. Our initial longitudinal MRI investigations demonstrated significant longitudinal gray and white matter tissue loss over a four-year interval even in healthy older adults (Resnick et al., J Neuroscience 2003). Recently, we confirmed and extended these findings over a longer (up to 9-year) follow-up interval (Driscoll et al., Neurology 2009). Furthermore, we demonstrated that a number of brain regions, including the hippocampus and orbital frontal region in addition to whole brain volume generally, showed accelerated tissue loss in individuals with mild cognitive impairment (MCI). We use support vector machine algorithms to develop classifiers for prediction of diagnostic status on an individual person basis. We identified a network of abnormalities that contributed to maximal discrimination between MRI scans of normal and MCI individuals in a sample of individuals matched for important demographic characteristics (Fan et al., Neuroimage 2008). We then applied this approach to the AD patients and controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and used the classifier based on that sample to calculate the Spatial Pattern of Abnormality for Recognition of Early AD (SPARE-AD) scores for all MRI scans of each individual BLSA participant. We demonstrated that higher SPARE-AD abnormality scores were associated with lower verbal memory performance (Davatzikos et al., Brain 2009) and that abnormality scores increased with age and cognitive impairment. Using the 11-C-PIB PET scan data, we confirmed the experience at other centers that 20-30% of cognitively normal older adults have PIB positive scans, i.e., deposition of brain amyloid. In addition, we investigated whether PIB retention was associated with longitudinal rCBF changes in the preceding years (Sojkova et al., 2008). PIB distribution volume ratios (DVR) of regions of interest were estimated by fitting a reference tissue model to the measured time activity curves (Zhou et al, Neuroimage, 2007). The mean cortical DVR was used to divide participants into high and low PIB retention groups. Both regions of greater longitudinal decrease and greater longitudinal increase in rCBF were observed in association with high PIB. While longitudinal declines may reflect greater decrements in neuronal function in the high PIB group, greater longitudinal increases in rCBF are also observed in those with higher amyloid load and may represent a compensatory attempt to preserve neuronal function in these regions. 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 (e.g. Iacono et al 2008). BLSA studies have shown that individuals with AD pathology at autopsy but without antemortem cognitive impairment (Asymptomatic AD) have larger nuclei and nucleoli of the anterior and posterior cingulate and the hippocampus, suggesting either a compensatory or inflammatory process. Ongoing studies investigate the cellular basis of neuroimaging findings, including regional volume loss, to try to better define characteristics that accelerate cognitive impairment as well as those that support the maintenance of cognitive health.