The fundamental cause of nearly every cognitive and neurodegenerative disorder remains unknown, but all forms of cognitive decline demonstrate both neuronal and cerebrovascular abnormalities. Current thinking has focused on oxidative damage by free radicals, the same mechanism accused of underlying cardiovascular disease and many cancers.(1-4) If indeed this process is operative, and all indications are that it is, then it is all the more likely to damage neural tissue since the brain and nerves utilize large amounts of oxygen while exhibiting reduced free radical scavenging capabilities over time. (5-8) Another, less direct mechanism has recently been proposed that may well function in conjunction with oxidative stress to promote neurodegeneration. Berislav Zlokovic at the University of Rochester Medical Center has compiled strong evidence that neurovascular degeneration plays an additional major, if not pivotal, role in generating nerve damage and that it operates through several mechanisms.(9)

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Diseases associated with an increased risk for cognitive disorders--such as diabetes mellitus, hypertension, ischemic heart disease, and hyperlipidemia, all known to increase the level of oxidative stress in the body--are also major causes of damage to the circulatory system, either large vessels, small vessels or both. (6,10-13) Therefore separating out the mechanisms and their respective roles requires diligent and exacting investigations. But the progress to be gained by discovering new methods to treat or prevent the resulting cognitive decline make all efforts worthwhile. Zlokovic identifies several new therapeutic targets already amenable to nutritional intervention that promise to slow cognitive decline over and above their already identified benefits.

There is strong evidence that diets rich in select herbs, fruits, and vegetables play a significant role in preventing cognitive decline over time. This effect is attributed only in part to known (antioxidant) compounds within whole foods. Additional benefits are believed to come from as yet unidentified components.(8,14-18) Many of these may well turn out to be beneficial to the neurovasculature.

Oxidative Stress and Neurodegeneration
Neurons are particularly vulnerable to free radical attack because:

• They have a low content of glutathione, a major antioxidant.
• Their membranes are rich in vulnerable polyunsaturated fatty acids, promoting lipid peroxidation activity.
• Brain metabolism consumes a great deal of oxygen.
• Neurons are post-mitotic (do not divide), limiting their ability to repair chromosomal damage.

Furthermore, neurons are increasingly sensitive to free radical attacks as one ages. Christen(19) explains that the brains of patients with Alzheimer's disease (AD) and other neurodegenerative disorders contain lesions typical of free radical damage including:

• DNA damage (It has been estimated that free radicals may modify approximately 10,000 DNA base pairs every day.(20)
• Protein oxidation
• Lipid peroxidation, and
• Advanced glycosylation end products.

Several factors contribute to the generation of free radicals. Brain trauma, for one, can result in free radical release and is a known cause for AD and dementia. Metals--iron, aluminum, mercury, copper, and zinc--all catalyze the generation of free radicals under certain circumstances. Particular attention is focused on the association between iron and the onset and progression of AD. The concentration of reactive iron, capable of generating hydroxyl radicals, is elevated in the brains of Alzheimer's patients. And iron, transferrin, and ferritin have a pattern of distribution similar to senile plaques and neurofibrillary tangles.(13)

To worsen matters, a positive feedback cycle is present in AD patients. Beta-amyloid aggregates, the signal lesion of AD, form free radicals in the presence of existing free radicals, leading to a cascade of damage. This beta-amyloid toxicity is reduced or eliminated by free radical scavengers including vitamin E, selegiline, and Ginkgo biloba, as well as desferrioxamine, an iron-chelating agent.(21-23)

In addition, mitochondrial anomalies associated with AD may also contribute to this free radical cascade. AD patients have more oxidative damage to mitochondrial DNA than to nuclear DNA, the end products of which appear particularly in the neurofibrillary tangles. (24)

There is also a genetic predisposition to lipid peroxidation. The E4 allele of apoliprotein E increases susceptibility, while the E2 allele appears to offer protection against neuronal cell death caused by hydrogen peroxide and beta-amyloid. The E4 isoform is also much more susceptible to free radical attack than the E2 isoform.(25,26) There are also genetic variants of amyloid that are more prone to neuronal and vascular damage.(9)

It is clear that oxidative damage has far reaching effects on numerous fundamental biochemicals. But the mechanics of degeneration do not end there. The integrity of both large and small blood vessels is compromised in multiple ways that contribute to and accelerate neural degeneration.

Neurovascular Mechanisms
According to Zlokovic,(9) the blood-brain barrier appears as central to the neurodegenerative process as it is to normal brain function. In this model, the brain is viewed as a large collection of neurovascular units composed of brain cells, blood vessels and a host of regulatory chemicals, neurotransmitters and membrane receptors. Regional blood flow to each neurovascular unit is exquisitely controlled to match supply with demand. Each tiny neurovascular unit responds to local neuronal activity by regulating not only blood flow but the transport of chemicals to and from brain tissue. The key element is the cells that line the capillaries. These vascular endothelial cells are uniquely arranged around the blood vessels in a pattern known as "tight junctions." Elsewhere in the body the spaces between these cells permit relatively free passage of materials, but within the brain this passage is severely restricted and tightly controlled, forming the blood-brain barrier (BBB). Practically every chemical that passes through this barrier does so by means of specialized transport systems. This includes nutrients into brain tissue and waste products out to the blood. One of these waste products is beta-amyloid, the peptide that accumulates in AD and may be instrumental in neuronal damage in other cognitive disorders as well.

Beta-amyloid is a small peptide that is soluble in interstitial fluid. Increased concentrations of beta-amyloid form the neurofibrillary tangles and senile plaques that are diagnostic of AD and are also found in other brain disorders. Whether this accumulation is primary or secondary is a matter of considerable interest and no current consensus. Initiating events can arise from any component of the neurovascular unit, making the precise origins of cognitive decline quite difficult to identify. Although the initial inciting lesion is debated, once begun in any arena, there are multiple interlocking pathways that can generate positive feedback loops to perpetuate and accelerate the processes of both neuronal and microvascular damage. Genetic variations of this peptide and of its production pathways can render subjects more than usually prone to vascular and/or neural toxicity. Any disease that impairs oxygenation or nutrition of tissues can begin the process. This includes aging of blood vessels, disruption of the BBB, atherosclerosis, chronic lung disease, anemia, malnutrition and many others. From any of these possible points of origin, cascades of cumulative damage can find multiple ways of developing.

Whole Food Protective Factors for Cognitive Disorders
Since oxidative stress and accumulation of free radicals over time are clearly involved in cognitive disorders, dietary and nutritional factors that decrease free radical production and its effects should theoretically lower risk for AD and other cognitive disorders.(27)

Many free radical scavengers are present in food, particularly fruits and vegetables. Strawberries and spinach have both been identified as being high in antioxidant activity.(28) In rats, diets high in antioxidant activity (strawberries, blueberries, and spinach) prevent the deleterious effects of oxidative stress on nerve growth factor and neuronal signal transduction.(29) In humans, dietary intake of fruits, vegetables, and vitamin C shows promise in preventing cognitive impairment, stroke, and vascular dementia.(30,31)

The incidence of Alzheimer's was also shown to be significantly lower in subjects who drank a moderate amount of wine (8-16 oz./day) than in non-drinkers, after controlling for demographics and other confounding factors.(32) This may be due to an antioxidant effect of resveratrol in red grape skin, since alcohol by itself is neurotoxic. Resveratrol has multiple beneficial effects including powerful antioxidant, antithrombotic and antiinflammatory activity and DNA protection.(33,34)

However, researchers studying spinach and strawberries as antioxidants find they have a greater effect than comparable antioxidant activity from vitamin E. They therefore propose that these foods contain phytochemicals with additional neuroprotective effects. (16) Flavonoids in these foods, for example, increase membrane fluidity, facilitating repair mechanisms in neuronal membranes.(8,18) Other researchers agree that phytochemicals possess many properties besides antioxidation. They are antiallergic, anti-inflammatory, antiviral, antiproliferative, and anticarcinogenic.(4,35-38)

To the above list, then, can be added the numerous foods that benefit both macro- and microcirculation, prevent abnormal blood clotting and retard atherogenesis. These include foods like garlic, green tea, fish oil, olive oil, organic grapes, kale, carrots, broccoli, blueberries, and cayenne peppers, in their original, unprocessed form, and red vegetables such as tomatoes that contain lycopene.

Final Thought
The research summarized above and supporting studies suggest that the use of certain natural foods reduces one's risk for neurodegenerative disorders and age-related cognitive decline through multiple mechanisms. This article advocates the use of whole foods. Most whole food-based nutritional supplements, on the other hand, are as yet unreliable in their content of active chemicals. In particular, those that contain bovine brain tissue pose potentially severe risks which may harm the very organ expected to benefit through the use of whole foods--namely, the brain.

© COPYRIGHT 2006 Dr. Gina Nick

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