Topics and Speakers Darryl C. De Vivo, MD
| ||||||
Synopsis
The human brain consumes fuel at a rate far exceeding any other organ. In a precisely orchestrated series of steps, fuels cross the blood-brain barrier and enter the brain, where they are used. But what happens when the brain is unable to utilize these fuels? In this lecture, Dr Darryl C. De Vivo first contrasts human brain development and its metabolism across the lifespan; discusses a current view on brain metabolism; then moves on to the pathophysiological and clinical consequences of defects in fuel availability, fuel transport and fuel combustion. Dr De Vivo concludes the lecture by describing treatments for these diseases.
The brain goes through a sequence of transformations from the prenatal period to adulthood. During the prenatal period, there is neuronal proliferation, neuronal migration, and the creation of the radial glial guide system. Then, from about 5 months of gestation and on through adulthood, there is a proliferation of the glial elements of the brain. Along with these transformations, there are notable differences between the infant brain and the adult brain. The first difference lies in body proportions. In the newborn infant, the brain is disproportionately large when compared to the rest of the body; body-to-brain ratio is 10 to 1. Afterward, brain weight increases rapidly during the first 2 to 3 years of life and is nearly at its fully developed size at age 3. From thereon, there is only modest growth. In adulthood, the body-to-brain proportions lie in a ratio of 50 to 1. A second difference lies in the metabolic rate. In adulthood, the metabolic rate is about half to 35% of what it was in childhood. Hence, the highest metabolic rate in the brain occurs during the first decade of life. Finally, a third difference lies in the rate of blood flow. In the newborn infant, blood flow and hence glucose utilization is about twice as much as in an adult brain; the oxygen consumption is also higher than in the adult brain. An interesting clinical consequence of this is that physicians often hear bruits when examining a child's brain, which should not be considered abnormal.
What are the brain's main sources of fuel during its lifespan? There are two sources: glucose and ketone bodies. The current view, proposed by Dr Magistretti, suggests that blood glucose crosses the blood-brain barrier, enters the brain, and is largely taken up by astrocytes. These astrocytes, in turn, either convert glucose to glycogen (for future use) or convert it to pyruvate through glycolysis. Pyruvate is then reduced to lactate, which is then exported to the neuron via extracellular space. The neuron utilizes the lactate, converts it to pyruvate, and then completely oxidizes it to CO2 and water; thereby generating ATP. Ketone bodies, an alternative fuel source, can also enter the brain through this pathway.
Until recently, the mechanism by which these fuels cross the blood-brain barrier was not understood. The brain does not allow water molecules in; only lipid soluble molecules can enter. Therefore, glucose, a highly water soluble molecule, should not be able to cross into the brain. New studies on the brain's transporter system have revealed that glucose enters the brain through facilitated diffusion, which allows a molecule to go down a gradient faster than by simple diffusion. The same process facilitates the transport of ketone bodies.
Cerebral energy failures result when the brain does not make or cannot use glucose or ketone bodies for fuel. Classification of cerebral energy failure syndromes includes defects in fuel availability, fuel transport, and fuel combustion. An example of a defect in fuel availability is a hyperinsulinemic condition. In the presence of excessive insulin, blood glucose will be driven down. In addition, the excess insulin will oppose the mobilization of fatty acids to the liver; if no fatty acids are presented to the liver, there will be no production of ketone bodies. The resulting absence of glucose and ketone renders the outcome(neuroglycopenia) generally poor. In this situation, there is 1 normal gene and 1 mutated gene for GLUT1, which results in difficulty in transporting glucose across the blood-brain barrier. The results vary mysteriously according to the individual: inability to walk, and seizures. Finally, an example of a defect in fuel combustion (or metabolism) is a defect in glycolysis. Defects in glycolysis are inherited and the symptoms are myopathic.
Dr De Vivo concludes the lecture with treatment options for these three kinds of disorders. For fuel availability disorders, blood glucose must be maintained at a constant level. Fasting should be avoided at all times. For fuel transport and fuel combustion disorders, a ketogenic diet, supplemented by coenzyme Q10 and L-carnitine, is suggested. However, since fuel combustion disorders are so rare, there has not been much experience in treating them.
