The Resilient Brain. Imaging Biomarkers of Brain Metabolic Reserve

这项提案旨在验证两个反映大脑对衰老弹性的创新生物标记物。生物标记物使用了两种广为人知的成像技术，磁共振成像(MRI)和正电子发射断层扫描(PET)，这两种技术目前都在动物和人类中使用。寻找衰老的生物标记物是一项困难的工作，因为它们的必要要求是预测力--理想情况下，在研究旨在调节衰老过程的干预措施时，我们希望尽快了解其对衰老轨迹的影响，而不必等待衰老过程最终发生。就大脑而言，如果我们能测量它的韧性，就可以做到这一点--而决定抑制细胞病理能力的一个相关生物参数是它的代谢储备。为什么是新陈代谢？在普通成年人中，大脑约占总体重的2%，但它却占到了所有能量消耗的20%，是仅凭其体重预测的10倍。请注意，只有休息状态才需要如此高的能量消耗率，而与任何精神活动相关的额外能量非常少，通常不到基线的5%。在这个高度活跃的器官中，代谢储备是大脑细胞仍然可以用来对抗所有我们称为衰老的病理现象的能量储备量。大量的新陈代谢储备将意味着对衰老的巨大适应能力，较差或没有储备意味着很少或没有适应能力。当测量能量储备时，我们希望以称为线粒体的小细胞器的功能为目标。关于线粒体有两个关键的观察结果。1)它们是执行有氧呼吸的蜂窝机器的基本元素，例如使用氧气将葡萄糖的产物氧化并将其转化为能量。2)线粒体的维持过程是高度动态的，这些成分尤其是那些较老的和受损的成分不断地更替。我们关注线粒体功能的这两个关键方面，并设计了两个措施。1)措施1-我们希望通过亚甲基蓝(MB)挑战前后的MRI测量细胞氧代谢来衡量线粒体的呼吸储备能力。甲基溴是一种化合物，已被批准用于人类，可导致细胞呼吸大幅增加(&gt；40%)。使用MB，我们可以将线粒体的容量扩展到它的极限，远远超过使用任何需要很少增量能量并且在实验或临床环境中难以控制的精神任务。2)测量2-我们希望测量一种特定线粒体蛋白的表达水平，称为18Kd转位蛋白或TSPO。TSPO调节线粒体的周转，并充当质量控制者，推动损伤或应激后移除有缺陷的线粒体的过程。重要的是，TSPO水平可以在活体内通过PET在动物和人类中进行测量。我们将通过跟踪两组大鼠来验证这些措施。其中一组大鼠将接受干预，这一干预已知有利于大脑老化过程，特别是线粒体功能。治疗将包括丰富环境和限制饮食，通过这些措施，我们将模仿人类健康的生活方式。在他们有生之年，我们将通过适当的测试持续监测他们的认知能力，并验证我们早期采取的措施是否可以预测他们的智力衰退。一旦得到验证，这些措施将成为老龄化研究的极其强大的工具。它们将缩短实验环境中的计时时间，并允许最佳利用动物，因为它们不需要动物牺牲。它们将立即被翻译到人类身上，因为成像技术和使用的药物挑战都已经单独验证和授权供人类使用。

This proposal aims to validate two innovative biomarkers of brain resilience to ageing. The biomarkers use two well-known and widely available imaging technologies, magnetic resonance imaging (MRI) and positron emission tomography (PET) that are presently used both in animals and humans. The quest for biomarkers of ageing is a difficult one as their necessary requirement is prediction power - ideally, when studying an intervention aimed at modulating the ageing process, we would like to know its effect on the ageing trajectory as soon as possible without having to wait for the ageing process to eventually happen. In the case of brain, this can be achieved if we can measure its resilience - and the one relevant biological parameter determining the ability to withhold cellular pathology is its metabolic reserve.Why metabolism? In the average adult human, the brain represents about 2% of the total body weight yet it accounts for 20% of all the energy consumed, 10 times that predicted by its weight alone. Note that this very high rate of energy consumption is required only by its resting state while the additional energy associated with any mental activity is remarkably small, often less than 5% of the baseline.In this highly energetic organ, metabolic reserve is the amount of energy reserve that brain cells can still use to fight all those pathological phenomena that we call ageing. Big metabolic reserve will then mean great resilience to ageing, poor or no reserve means little or no resilience.When measuring energy reserve we wish to target the functioning of small cellular organelles called mitochondria. There are two key observations about mitochondria. 1)They are the fundamental elements of the cellular machine performing aerobic respiration e.g. using oxygen to oxidise the products of glucose and convert them into energy. 2) The process of mitochondria maintenance is highly dynamic with a constant turnover of these components particularly the older and damaged ones.We have focused on these two key aspects of mitochondrial function and devised two measures.1) MEASURE 1 - We wish to measure mitochondrial respiratory reserve capacity by measuring oxygen cellular metabolism with MRI before and after a challenge with Methylene Blue (MB). MB is a compound, already authorized for human use, that induces substantial increases (>40%) in cell respiration. Using MB we can expand mitochondrial capacity to its limit, far more than using any mental task that requires very little incremental energy and is far less controllable in an experimental or clinical setting. 2) MEASURE 2 - We wish to measure the level of expression of one particular mitochondrial protein, called the 18Kd translocator protein or TSPO. TSPO regulates mitochondrial turnover and acts as a quality controller driving the process that removes defective mitochondria following damage or stress. Importantly TSPO levels can be measured in-vivo by PET in both animals and humans. We will validate these measures by following through time two groups of rats. One group of rats will be submitted to an intervention which is known to benefit the brain ageing process and mitochondria function in particular. The treatment will consist in environmental enrichment and dietary restriction by which we will mimic human healthy lifestyle. During their lifetime, we will continuously monitor their cognitive ability using appropriate tests and we will verify whether our measures, taken early on, predict their mental decline. Once validated, these measures will be extremely powerful tools for ageing research. They will shorten timings in experimental settings and will allow an optimal use of animals as they do not require animal sacrifice. They will be immediately translated to humans as both imaging technologies and the pharmacological challenge used have been separately validated and authorized for human use.