The Resilient Brain. Imaging Biomarkers of Brain Metabolic Reserve

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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.