The term "neurodevelopmental disorders" encompasses a large group of neurological disorders that become evident during periods of brain maturation. They frequently share complex neurological features including various learning disabilities and complex behavioral features. These disorders become evident in early childhood and tend to persist into the adult lifespan. Included in this constellation of disabilities are autism, ADD (attention deficit disorder) and pervasive developmental disorder. It is believed they are caused by genetic mutations and environmental factors.

Alterations in the configuration, wiring and connectivity of the developing brain are key contributors. There are specific periods during brain formation where certain influences can produce significant functional alterations that might be insignificant if they first occurred in adults.

Fetal and perinatal programming experiments in animals have documented persistent abnormalities in glucocorticoid receptors and signaling in offspring related to variations in maternal care that engender the perception of stress in the offspring. This alters stress responsivity -- changes that persist into adulthood. Many of the mutations that cause developmental disorders disrupt genes that are also expressed in the adult brain. This insight is significant because in addition to the developmental affects they cause in the brains of young children, it is possible that altered function of these genes may produce additional effects in adulthood (additive to those changes in brain wiring produced during the formative years).

This very possibility has been investigated in animal models of human neurodevelopmental disorders. Results suggest that persistent expression of the genes that caused the disorder to manifest initially during childhood may contribute to cognitive or behavioral problems in adults. These studies support the concept that treating the disrupted molecular mechanisms in adults might result in functional improvement. It has even been speculated that biochemical improvement of the underlying genetic defects may produce metabolic changes that allow adult neuroplasticity mechanisms to compensate for certain of the characteristic developmental problems.

The animal studies have investigated models of neurofibromatosis, a disorder in which neurological symptoms including attentional issues, deficits in executive function and learning disabilities are produced. One of the effects of the NF (neurofibromatosis) gene is to interfere with specific cellular signaling pathways. This results in the activation of Ras-signaling pathways.

There are pharmacological interventions that can reduce the isoprenylation of Ras, thereby tending to normalize this vital signaling pathway. HMG-CoA reductase inhibition with the drug lovastatin (a cholesterol-lowering drug) is one such intervention. Notably, short pharmaceutical treatment of animals with NF using lovastatin reduces the cognitive impairments in these animals while having no effects on control animals. When tested in humans, a 12 week treatment with simvastatin improved performance on a neuropsychological test. Moreover, the treatment protocol had the most robust beneficial effect on patients with the worst baseline status.

Similar benefits using this molecular approach have been observed in animal models of other neurodevelopmental disorders including Down's syndrome, Rubenstein-Taybi syndrome (another genetic disorder that is characterized by intellectual disorders, and specific physical features such as broad thumbs and and toes), Tuberous sclerosis, Fragile X syndrome (associated with learning disabilities, autism, ADD (attention deficit disorder) and epilepsy) and Rett syndrome.

The obvious conceptual epiphany in this approach is the ability to improve functional indicators in adults with neurodevelopmental disorders long after the brain has matured. Many of these disorders are common and disabling. They also have limited treatment options.

In BACE-ball and your brain I discussed how energy shortages in the brain tend to increase the activity of an enzyme (BACE1) that speeds up the activation of APP (amyloid precursor protein). This increases the formation of A-beta (for beta amyloid), which is associated with the development of Alzheimer disease. Thus, energy brownouts are to be avoided at all costs. Dr. Robert Vassar, the lead author of this insightful article, linked deficits in energy generation in the brain with the development of narrowing of the arteries to the brain.  Oxygen and nutrients such as the major brain fuel glucose are delivered to nerve cells via the circulatory system. When blood flow is restricted, these vital compounds don't get where they need to go and brain cells suffer. One result is impaired energy generation and activation of BACE1.

Another interesting paper that relates to this very issue was recently published in the medical journal Brain Research (1226 (2008): 209-219). It further investigates the connection between power brown outs in the brain and A-beta formation. The investigations were performed in very old dogs who spontaneously produce A-beta in their brains.

The authors noted that localized declines in cerebral glucose metabolism are an early and progressive feature of Alzheimer disease. They state that such declines occur long before symptoms develop and, as such, offer a window of time for medical intervention. Medium chain triglycerides (MCTs) are rapidly turned into ketone bodies in the liver and ketones are used efficiently in the brain as an optional fuel source. Noting this, they provided a nutritional product (MCT oil) that can generate this alternative fuel (ketones) for the brain when glucose is in short supply or is not being used efficiently. In their study, dogs were supplemented with MCT oil for several months and brain metabolism was subsequently investigated.

They documented that aged dogs receiving the MCT therapy showed markedly improved mitochondrial (mitochondria are the small intra-cellular inclusions that generate energy) function. The effect was most prominent in the parietal lobe region. This is where early decreases in glucose use tends to occur in patients with Alzheimer disease. APP levels also decreased. There was also a trend towards a decrease in total A-beta in the parietal lobes of the treated dogs.

What this tells us is that energy generation was improved and with it APP and A-beta levels fell. These results are consistent with the hypothesis that brain cell energy failure (an inciting cause of Alzheimer disease) can trigger the buildup of A-beta, which ultimately leads to neurodegeneration. Furthermore, they suggest that by supplying another fuel source for the neurons to use, the process can be reversed with beneficial results. The take home message might be that for anyone at risk for such diseases, that chronic supplementation with MCT oil might be a prudent preventative intervention.

Alzheimer Disease (AD) and a host of other so-called neurodegenerative diseases such as Parkinson Disease and Lou Gehrig Disease (also called ALS -- for Amyotrophic Lateral Sclerosis -- a wasting disease that tends to affect motor nerves and secondarily muscle function in the arms and legs as well as the swallowing and breathing muscles) have been refractory to treatment largely because the exact cause of each of these devastating disorders is unknown. They have been the subject of intense research to no avail -- that is until recently. A remarkable paper was recently published in the medical journal Neuron. The lead author was Dr. Robert Vassar from Northwestern.

The purportedly toxic compound that builds up in the brains of persons afflicted with AD is called beta-amyloid (A-beta for short). It is produced by the cleavage of amyloid-beta precursor protein (APP) by the action of beta-site APP cleaving enzyme 1 (BACE1). This accelerates the buildup of A-beta. The level and activity of BACE1 are increased in the brains of AD patients. This led to the idea that the chronic increase in BACE1 in the brain may contribute to the development of AD.

This is not of much help to those persons at risk for this devastating disease unless something can be done about it. From a pharmaceutical perspective, such hope is on a distant horizon. However, an interesting observation might provide a clue as to what leads these sticky amyloid fibrils to form and aggregate. This insight was identified by the application of several metabolic manipulations that each decreased energy generation in neurons. One involved impairing the electron chain, which is the main conveyor belt that turns food into energy. Another was a potent inhibitor of an enzyme in the glucose metabolic pathway, while yet another manipulation involved administering an overdose of insulin to the lab animal. This latter model of energy impairment caused cerebral brownouts by causing blood glucose levels to fall to markedly subnormal levels. This prevented the neurons from accessing their primary fuel -- glucose.

The common thread in each of these models was an increase in BACE1 and the accumulation of A-beta.

The researchers suggested that physiologic changes that increased blood flow to the brain, which would deliver more oxygen and more glucose, would enhance energy production and lessen A-beta via a beneficial effect on BACE1. What they omitted to mention is that many neuroscientists are starting to refer to AD as Type 3 diabetes because of the presence of a similar inability of the brain to take up and metabolize glucose as that which exits in the tissues of the body in Type 2 diabetes (the type generally associated with obesity). This is significant because diabetes is a metabolic disorder that responds to various lifestyle factors that stabilize blood sugar swings and enhance insulin sensitivity. These same interventions would be expected to enhance cerebral glucose metabolism and act to alleviate energy shortages, BACE1 activation and accumulation of A-beta, the alleged culprit behind the initiation of AD.

These findings are consistent with a reversible etiology of one of the primary modern day medical scourges. One that we may ameliorate by making appropriate lifestyle choices that are easily within our control.