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Age Associated Mental Impairment

By Ronald Steriti, ND, PhD

Description

Many people experience a progressive decline in overall cognitive function as they age. Often this begins with a loss in their ability to store and retrieve from short-term memory and to learn new information that progressively worsens over the years.

Simple problems if not addressed can, over time, progress. Many neurological diseases are more common in older people. Cognitive function can be impacted in several ways, including:

·      The damaging effects of years of free radical exposure (oxidative stress).

·      Changes in lifestyle and diet leading to nutrient deficiencies (i.e. many older people no longer cook their own meals)

·      Hormonal imbalances and decreased levels of key hormones, especially pregnenolone, DHEA and melatonin

·      Decreases in oxygen available to brain cells because of impaired circulation due to pathology (for example, atherosclerosis or heart disease) or a lifetime of poor health habits (for example, smoking, drinking, drug abuse, limited exercise, poor diet, or stress)

·      Declining energy output of brain cells

·      Essential fatty acid deficiencies (the brain is composed almost entirely of fatty acids)

Conventional medicine has little to offer for people that begin noticing a small decline in their memory and mental abilities. Often these changes are attributed as being a natural or inevitable part of growing old.

Forms

Age-associated neurological impairment can take a variety of forms including memory loss, senility, and dementia. Dementia, a general term for diseases involving nerve cell deterioration, is defined as a loss in at least two areas of complex behavior-are as including language, memory, visual and spatial abilities, and judgment-so as to interfere with a person's daily living. Dementia, the most serious form of age-associated mental impairment, is often a slow, gradual process that may take months or even years to become noticeable. Symptoms vary depending on which areas of the brain are affected.

It is important to distinguish between normal, age-associated mental impairment from conditions such as dementia that signal a disease process. Not all memory difficulties or cognitive complaints indicate the presence of Alzheimer's disease or any mental disorder. Many memory changes are temporary and are linked to environmental factors such as stress rather than to physiological (bodily) processes. It is also common for older people and those around them to notice memory lapses and to be more concerned about them than younger people, when in fact those lapses may not be any different from those of a younger person who misplaces her keys.

At the same time, serious cognitive difficulties should not be dismissed as unavoidable consequences of aging. A helpful guideline is that many people with serious mental impairment do not recognize or will not admit that they have a problem, while it is obvious to those around them. The recommendations given in this protocol can help age-associated mental impairment of any form or cause, but significant impairment arising from diseases such as stroke should be treated with the help of medical professionals.

Causes

Age-associated mental impairment can have a variety of causes beyond overall aging. Conditions that affect the brain and result in intellectual, behavioral, and psychological dysfunction include:

Medication side effects.

Adverse side effects can result from too high or too low a dosage of medications, unusual reactions to medications, or combinations of medications. It is especially common in the older population for individuals to be taking many different medications prescribed by different doctors, in addition to over-the-counter supplements. Be certain that your primary physician is aware of all prescription and nonprescription medications that you take.

Substance abuse.

Abuse of drugs (legal or illegal) and alcohol can cause mental impairment. Older people are less able to tolerate and recover from the use of such substances. Alcohol also causes liver damage, increasing the risk of liver disease, which often leads to dementia.

Metabolic disorders.

Thyroid problems, anemia, and nutritional deficiencies-common in older people who have less appetite and less energy to cook and shop, and who absorb fewer nutrients from the food they eat-have a negative impact on mental function. These problems may go undetected in older people when symptoms are attributed to aging (see Thyroid Deficiency and Anemia protocols).

Neurological disorders.

Multiple sclerosis (see Multiple Sclerosis protocol) and normal-pressure hydrocephalus (increased fluid in the brain) are examples of conditions that affect mental function.

Infections.

The brain is susceptible to viral, bacterial, and fungal infections. One extremely rare infection of the brain that causes dementia is Creutzfeldt-Jakob disease, transmitted by a special protein (prion) that damages tissue as it replicates.

Trauma.

Head trauma can result in transient (concussion) or lasting mental impairment. Trauma is obvious in most cases based on history and examination. One type of head trauma frequent in older people, however, is not always obvious. It is called a subdural hematoma, which means that blood is leaking into the tissues around the brain. This type of injury can occur after very minimal trauma, and its onset can be very gradual if the leak is small. Symptoms such as headache, confusion, and lethargy, are often nonspecific.

Toxic factors.

Exposure to substances such as carbon monoxide and methyl alcohol can cause mental impairment.

Hormonal changes

Medicine is only beginning to understand the hormonal changes that accompany aging. In women a fairly sudden drop in the hormone estradiol leads to menopause (see Menopause protocol). In addition to symptoms such as hot flashes, decreased bone density, and vaginal dryness, symptoms of altered mental function like mood swings, nervousness, and fatigue are common. In men, testosterone levels decrease gradually over time, leading to decreased muscle tissue and bone density, increased abdominal fat and cholesterol, deteriorating heart function, and psychological and sexual changes that can impact mental function. In both sexes, the level of the hormone dehydroepiandrosterone (DHEA) falls precipitously with age. Imbalances in hormones, particularly DHEA and pregnenolone, can profoundly affect mental function. [1]

Tumors

Abnormal tissue growth (tumors) in the brain can be either primary (originating in the brain itself) or metastatic ("seeds" of tissue that originated in a tumor in another part of the body, and that have traveled to the brain and begun to grow). Metastatic tumors are more common. Approximately 70% of brain tumors are benign. (Also see Cancer protocols.)

Depression

Depression, stress (see Stress and Depression protocols), and grief are common causes of mental impairment that are transient and treatable. Depression in older people is often overlooked because symptoms are confused with those of a medical illness. Depression is also considered a normal part of aging: the National Mental Health Association reports that over 58% of older adults believe depression accompanies aging. Although older adults may have difficult experiences such as changes in health status, relocation, or loss of loved ones, if the sadness that follows one of these life changes lingers for a long period of time, it may be diagnosed as clinical depression.

Late-life depression affects about 6 million people, most of them women, but only about 10% of them ever receive treatment for their condition. Depression has serious consequences. It takes the pleasure out of daily life, aggravates other medical conditions, and can lead to suicide. In fact, older adults are considered the group most at risk for suicide. (The suicide rate in older adults is more than 50% higher than the rate for the nation as a whole.) Mental illnesses can also impair mental functioning.

Circulatory Disorders

Circulatory disorders, such as heart problems or stroke can restrict the oxygen available to brain cells by reducing blood flow. Also, many people who feel fine may have a buildup of plaque in their arteries (atherosclerosis), which can eventually limit the oxygen supply to the brain.

The most common type of stroke is called an ischemic stroke. This means that a blood clot has traveled to the brain where it has lodged in a vessel so that brain cells have died from lack of oxygen. In a hemorrhagic stroke a vessel bursts, flooding brain cells with blood. Transient ischemic attacks (TIAs) are miniature strokes caused when blood flow is blocked to a variable extent for a few hours or a day but is then restored, causing no permanent damage. TIAs are an important warning signal that treatment is necessary to prevent a more serious stroke.

Strokes occur most often in older people: three fourths occur in people over age 65. Symptoms depend on the part of the brain affected, but can include difficulty moving, talking, and thinking. The Stroke protocol describes the acute care of strokes, in other words, what to do right after a stroke has occurred. The recommendations contained in this protocol will help to improve long-term recovery of mental function, such as memory, attention, and learning. It should be noted that normal aging creates a perfusion (circulation) deficit in the brain, so nutrients and drugs that improve cerebral circulation are of critical importance to even healthy humans as they grow older.

Monoamine Oxidase

Another cause of brain aging is the elevation of an enzyme in the brain called monoamine oxidase (MAO). Monoamine oxidase A and B are the primary enzymes that degrade neurotransmitters in the central nervous system and peripheral tissues. Elevated MAO levels damage brain cells and are a specific cause of age-related neuronal deterioration. Too much MAO has also been shown to cause pathological disorders such as Parkinson's disease. [2, 3]

Risk Factors

Mid-Life Blood Pressure

A 30-year study of male twins showed that elevated blood pressure in mid-life predisposed men to accelerated brain aging and an increase risk of stroke later in life. Men with even mildly elevated blood pressure 25 years before showed smaller brain volumes and more strokes compared to their twin brothers who did not have the elevation in blood pressure. This study, published in the journal Stroke, emphasized the importance of aggressively treating elevated blood pressure even if it is not grossly abnormal. Refer to the Foundation's Hypertension protocol for information about blood pressure control therapies and diets. [4]

Lifestyle

Taking steps to improve overall health is highly recommended to prevent or minimize age-associated mental impairment. For example, exercising regularly, not smoking, and monitoring blood cholesterol level can reduce the risk of stroke and heart disease and keep arteries open, supplying the brain with oxygen and nutrients. Regular exercise improves some mental abilities by an average of 20 to 30%. Abstaining from alcohol or drug use, or minimizing it, can also help preserve mental function. Since people tend to eat less food as they age, the use of low-fat, nutrient-rich foods is recommended. Such a diet will help prevent nutrient deficiencies, which can impair mental function through physical illness.

Innovative Drug Strategies

Piracetam

Piracetam is considered to be the “father” of nootropic drugs (cognitive enhancers.) Piracetam has been shown to improve a whole series of mental activities, especially higher cortical functions. It can improve your intelligence, concentration, memory and creativity. Piracetam is a cyclic derivative (2-oxo-pyrrolidine acetamide) of the amino acid GABA (gamma amino butyric acid). Although GABA is an inhibitory neurotransmitter, piracetam does not appear to act in the same way.

Piracetam has been shown in studies spanning three decades to:

Enhance memory, particularly when used in combination with choline [5-7]

Increase attention and cognition [8]

Improve spatial learning [9]

Improve the use of glucose by the brain [10, 11]

Improve brain circulation [12]

Reduce lipofuscin (age pigment) buildup in the brain [13]

Act as an antioxidant [14]

In animal experiments and in single-photon-emission tomography (SPECT) studies of patients with acute ischemic stroke, piracetam improved micro-circulation and neuronal metabolism, and enhanced transmitter functions. [15]

Another study found that piracetam provides neurological and functional protection against deficits resulting from a moderate or severe stroke when administered within a few days. This study noted that piracetam is well-tolerated and is effective when taken orally and that other treatments have very limited efficacy. [15-17]

Research has demonstrated that piracetam's effect on circulation in the brain translates into improvements in aphasia (inability to speak) and level of consciousness, as well as fewer deaths. [18]

A daily dose of 4,800 mg of piracetam proved to be very effective in a double-blind study of 60 patients with post-concussional syndrome of 2-12 months' duration. After 8 weeks of treatment, piracetam significantly reduced the occurrence and severity of vertigo, headache, tiredness, decreased alertness, increased sweating and neurasthenic symptoms. [19]

A study published in the journal, Clinical Nuclear Medicine showed that after 2 months of oral treatment with piracetam (2.4 g daily) in elderly human volunteers, SPECT imaging of the brain indicated a regional improvement in cerebral blood flow, particularly in the cerebellum. However, no beneficial effects with this drug were spontaneously reported. [20]

Unfortunately, piracetam has not been approved by the FDA for any use, despite its long track record and extensive clinical use in Europe. Piracetam is not available in the US. It can be ordered from offshore pharmacies (see below). The recommended dose of piracetam is 2,400 to 4,800 mg a day.

Hydergine

Hydergine is approved by the FDA to treat individuals over age 60 who manifest signs or symptoms of mental incapacity. Unfortunately, when one study showed that Hydergine was not effective in treating Alzheimer's disease, American physicians virtually stopped prescribing Hydergine, even though the drug was never approved for the treatment of Alzheimer's disease.

Hydergine remains a popular supplement among health conscious people seeking to slow age-related mental decline. Recent studies have revealed several mechanisms by which Hydergine protects against brain aging by several mechanisms, including:

·      Increase blood supply and oxygen to the brain [21]

·      Enhance metabolism in brain cells [21]

·      Protect the brain from damage during periods of decreased or insufficient oxygen supply. [22]

·      Slow the deposit of age pigment (lipofuscin) in the brain. [23]

·      Prevent free radical damage to brain cells. [24]

·      Increase intelligence, memory, learning, and recall. [25]

·      Enhance the use of glucose by brain cells. [26]

·      Normalize the brain levels of serotonin.[27]

·      Increase superoxide dismutase (SOD) and catalase in the brain while decreasing toxic levels of monoamineoxidase (MAO). [28]

Autoantibodies

An article published in the journal Life Science discussed specific antibodies that bind to brain cell membranes and then target the cell for destruction and removal by the immune system.

Younger brains have significantly lower levels of these destructive antibodies compared to older brains. Hydergine-treated mice showed a reduction in these destructive antibodies, suggesting that middle-aged people who take Hydergine could retard the development of senile dementia caused by programmed immune destruction. The animals receiving Hydergine in middle-age maintained healthy brain cell metabolic activities compared to the control group who did not receive Hydergine.

The scientists concluded that Hydergine therapy begun in middle age could protect against the initiation of the cascade that leads to Alzheimer's disease. The scientists emphasized that once the Alzheimer's disease cascade begins, Hydergine would be of little value as the brain cells have already been marked and targeted for immune destruction.  [29]

Studies

An article published in the Journal of the American Geriatric Society described a double-blind study that evaluated the effectiveness of Hydergine versus papaverine in the treatment of selected symptoms associated with mental aging. After 12 weeks of treatment, ratings of overall clinical condition and global change showed that the 26 patients given Hydergine improved more than twice as much as the 27 patients given papaverine. [30]

The Life Extension Foundation has long advocated the use of Hydergine to prevent the degenerative changes that lead to brain cell aging and Alzheimer's disease. Hydergine appears frequently in the scientific literature as therapy for a wide range of diseases ranging from asthma to stroke. Hydergine may be the most under-utilized drug in the United States because of one study that showed its failure to treat advanced Alzheimer's disease.

The recommended dose of hydergine is 4 to 10 mg a day.

In 5% of people, Hydergine can induce a mild state of nausea. These people should use Sandoz brand Hydergine LC, an enteric-coated capsule that bypasses the stomach and prevents nausea. The problem with these capsules is that they only come in strengths of 1 mg. For the remaining 95% of people for whom Hydergine does not cause nausea, European suppliers sell 5 mg Hydergine tablets that make taking high doses of Hydergine convenient and very economical.

Deprenyl

Low-dose deprenyl (Selegiline) is thought to protect against brain aging by specifically inhibiting monoamine oxidase B (MAO B) in the brain. MAO degrades the neurotransmitters norepinephrine (which is formed from dopamine) and serotonin (which is formed from tryptophan).

Deprenyl was approved for use in Parkinson’s disease in the 1980s and was often combined with L-dopa (levodopa). One study, however, raised concerns over combining high doses of deprenyl (10 mg per day) with L-dopa due to an apparent increase in mortality in the deprenyl group. [31] The results of that paper were hotly debated and several flaws were found in the study design. Later studies showed clinical benefit with deprenyl without a decrease in mortality, and no toxic effects, particularly when low doses were used (10 mg per week). [32-34]

Deprenyl is recommended in very low doses (10 mg a week) as part of Life Extension’s anti-aging protocol. More information about deprenyl, it’s actions, uses and controversy can be found in The Physician’s Guide to Life Extension Drugs.

Deprenyl has been shown to stimulate the efflux of norepinephrine, dopamine, and serotonin in vitro by a direct action on the hypothalamus. Some researchers are proposing that deprenyl may be considered as an alternative to levodopa for starting treatment in Parkinson's disease patients. [35, 36] 

Deprenyl has also been shown to induce rapid increases in nitric oxide (NO) production in brain tissue and cerebral blood vessels and also protect the vascular endothelium from the toxic effects of amyloid-beta peptide. [37]  A recent study showed that deprenyl protected cells from apoptosis induced by a neurotoxin, N-methyl(R)-salsolinol, and reactive oxygen species, nitric oxide and peroxynitrite. [38]

Zhu et al., showed that deprenyl significantly improved the cognitive function of rats after traumatic brain injury. [39]

A study of 17 patients with Alzheimer’s disease found that the Mini-Mental State Examination scores were significantly higher in those patients receiving Selegiline (deprenyl) than in those receiving placebo.[40]  In India, a study of 32 patients with Parkinson’s disease found a significant improvement in memory with patients treated with 10 mg a day of deprenyl as compared to placebo. [41]

The ideal human dose of deprenyl to slow brain aging has been estimated to be about 1.5 mg a day by scientists who have conducted life-span studies on the drug. Since deprenyl is usually sold in 5-mg tablets, and has a long-acting effect on the brain, most Life Extension members take the low dose of 5 mg of deprenyl twice a week.

Hydergine, on the other hand, seems to be more effective when higher doses are used. European doctors often prescribe 4.5 to 20 mg a day of Hydergine without concern for toxicity.

High-dose Hydergine and low-dose deprenyl have been used together for more than 15 years by people seeking to protect against neurological aging and boost cognitive function. No adverse effects have been reported when using these two medications together.

Care should be taken when administering dopamine to patients that have been using deprenyl. One article noted a drastic increase in systolic blood pressure after a critically ill man using Selegeline was given an infusion of dopamine. [42]

For middle-aged people who have a family history of Alzheimer's disease, a daily dose of 10 to 20 mg of Hydergine is suggested. For middle-aged people seeking to slow their rate of brain cell aging, a daily dose of 5 mg to 10 mg of Hydergine is suggested.

Nimodipine

Nimodipine is especially recommended for head trauma victims. Nimodipine (brand name Nimotop) is a calcium channel blocker specific to the central nervous system. It prevents movement of calcium into the cells of blood vessels, thereby relaxing the vessels and increasing the supply of blood and oxygen. It dramatically improves cerebral blood flow.

Nimodipine is an FDA-approved drug used to prevent and treat problems caused by a burst blood vessel around the brain but has been ignored by most neurologists treating victims of stroke and other age-related neurological diseases.

An article published in the journal Neurology Science described a 26 week, multi-national, double-blind, placebo-controlled study of nimodipine in patients with multi-infarct dementia. This study failed to show a significant effect of nimodipine on cognitive, social or global assessments. However, a lower incidence of cerebrovascular and cardiac events was observed in the nimodipine-treated patients in comparison with the placebo group. A subgroup analysis found that those with patients with subcortical vascular dementia performed better on the majority of neuropsychological tests and functional scales in comparison with patients on placebo. [43, 44]  The recommended dose of nimodipine is 30 mg, three times a day.

Centrophenoxine

Centrophenoxine (meclofenoxate) is widely used in Europe in combination with piracetam to improve memory and enhance mental energy.  Centrophenoxine is widely available in Europe, but is not sold in the United States. It can be ordered from a pharmacy in Europe (see below for more information).

Researchers have proposed several mechanisms for Centrophenoxine, including:

Increasing activity of free radical scavengers, especially in brain and heart tissues. [45]

Providing antioxidant action, possibly due to the DMAE (dimethyl-amino-ethanol) it contains. [46]

Increasing acetylcholinesterase activity in the hippocampus and brain. [47]

Decreasing the deposition of the age-pigment, lipofuscin, which has been shown to cause neuronal damage.  [48]  

Inhibiting total MAO (monoamine oxidase), MAO-A and MAO-B, which  have been shown to damage brain cells.  [49] Recall that

Increasing the content of serotonin (5-HT), a key neurotransmitter  that can be damaged by elevated MAO. [50].

Significantly increasing the fluidity of brain membranes, which can reverse the dehydration of nerve cells of older animals. [51, 52]

Centrophenoxine was shown to improve memory retention in aged rats in tests using the maze method for active avoidance with punishment reinforcement and the step-through method for passive avoidance with negative reinforcement. Centrophenoxine increased the number of responses to conditioned stimulus and strongly prolonged the time spent in the light chamber (a measure of improved retention).  [53] 

A double-blind clinical trial of 50 patients with dementia examined the effects of 2 grams a day of Centrophenoxine for 8 weeks. 48% of the Centrophenoxine group displayed improvements in the memory functions versus 28% of the placebo group. [54]

One study found that Centrophenoxine corrected the blood pressure drop when standing, in 25 patients that had orthostatic hypotension due to brainstem ischemia. [55]

The recommended dose of Centrophenoxine is 250 to 1000 mg a day.

Nutritional Supplements

Acetylcholine Precursors

Phosphatidylcholine

The most commonly used memory-enhancing nutrients are choline, lecithin, and phosphatidylcholine, which are precursors to the chemical neurotransmitter acetylcholine that carries messages between brain cells. Because acetylcholine helps brain cells communicate with each other it plays an important role in learning and memory. Acetylcholine deficiency can predispose a person to a wide range of neurological diseases, including Alzheimer's disease and stroke.

One study found that phosphatidylcholine administered with vitamin B12 improved the memory of rats in which brain damage had caused memory impairment.  [56]

A recent study published in the journal Parenteral Enteral Nutrition examined the effects of choline chloride when given to patients receiving total parenteral nutrition (TPN). Significant improvements were found in the delayed visual recall of the Weschler Memory Scale-Revised, and borderline improvements were found in the List B subset of the California Verbal Learning Test (rote verbal learning ability) and the Trails A test (visual scanning, psychomotor speed and set shifting). The authors concluded that both verbal and visual memory may be impaired in patients who require long-term TPN and both may be improved with choline supplementation. [57] 

Choline, lecithin, and phosphatidylcholine are best taken early in the day to maximize improvement in brain productivity throughout the day. Suggested dosage ranges are 1,000 to 3,000 mg a day of choline or 10,000 mg a day of lecithin, and/or 100 to 600 mg a day of phosphatidylcholine.

NADH

NADH (Nicotinamide adenine dinucleotide) is a coenzyme that acts as an electron carrier in the body. A recent study concluded that nicotinamide enhances brain choline concentrations by mobilizing choline from choline-containing phospholipids. [58, 59]

The recommended dose of NADH is 5 to 10 mg a day.

Ginkgo Biloba

Extracts from Ginkgo Biloba, the "maidenhair tree", have been shown to thin the blood and improve blood flow to the brain, protect against free radicals, and improve memory. Ginkgo biloba is approved in Germany for the treatment of dementia. There are over 1,200 published studies in the scientific literature on ginkgo biloba extract. [60-62]

An article published in the journal Physiology and Behavior showed that treating rats with ginkgo biloba extract not only improved their brain function (learning and memory) but also significantly extended their life-span. Those rats fed ginkgo biloba took fewer training sessions to reach the performance criteria as well as fewer errors in an eight-arm radial maze. [63]

Treatment with ginkgo biloba extract can also partially prevent certain harmful, age-related structural changes as well as free radical damage to the mitochondria (where energy is produced in a cell) in the brains of old rats. [64]

In one study, patients with memory disturbances were supplemented with ginkgo biloba. Following ginkgo treatment, 15% of patients reported the total absence of memory disturbance symptoms, and 62% reported that the remaining symptoms were mild to moderate. [65]

The recommended dose of ginkgo biloba extract is 120 mg per day.

Essential Fatty Acids

Essential fatty acids serve as the basic building block of nerve cells and are used as fuel for brain metabolism. They are used to make prostaglandins which regulate inflammation in the brain. About 75% of myelin (the sheath that covers nerve cells) is composed of fats.

DHA

Docosahexaenoic acid (DHA) is a long chain omega-3 fatty acid that is present in high concentrations in the central nervous system. Fish oil contains both EPA (eicosapentaeonic acid) and DHA.

DHA supplementation was found to significantly decrease the number of reference memory errors and working memory errors in aged male rats and in young rats fed a fish oil-deficient diet through three generations. The authors of the study proposed that the mechanism was due to the ability of DHA to reduce the levels of lipid peroxide in the hippocampus. [66, 67]

Brain Cell Energy Boosters

The brain requires a lot of energy to perform it’s myriad of functions. An effective memory enhancement technique involves boosting the energy output of brain cells. With aging there is a decline in the ability of neurons to take up glucose (the primary fuel for the brain) and to produce energy. This decline in energy production not only causes memory and cognitive deficits but also results in the accumulation of cellular debris, which eventually kills brain cells. When enough brain cells have died from accumulated cellular debris, senility is usually diagnosed.

Acetyl-L-carnitine

About 95% of cellular energy production occurs in the mitochondria. Many diseases of aging are increasingly being referred to as "mitochondrial disorders". Acetyl-L-Carnitine is the biologically active amino acid involved in the transport of fatty acids into the cell's mitochondria for the purpose of producing energy. Acetyl-L-carnitine is sold as an expensive drug in Europe to treat heart and neurological disease.

Acetyl-L-carnitine can increase muscle mass and convert body fat into energy. It has been shown to protect brain cells against aging related degeneration and to improve mood, memory, and cognition. Many people use acetyl-L-carnitine to maintain immune competence and reduce the formation of the aging pigment lipofuscin. The most important effect of acetyl-L-carnitine, however, is to maintain the function of the cell's energy powerhouse, the mitochondria.

A recent article published in the journal Neurochemical Research examined the anti-aging effects of acetyl-L-carnitine on Fischer rats. The study showed that long-term feeding with acetyl-L-carnitine was able to reduce the age-dependent increase of both sphingomyelin and cholesterol cerebral levels with no effect on the other measured phospholipids. [68]

Another study published in the American journal Otology examined the effects of acetyl-L-carnitine on age-associated hearing loss in Fischer rats. Acetyl-L-carnitine and alpha-lipoic acid were found to reduce age-associated deterioration in auditory sensitivity and improve cochlear function. The effect appeared to be related to their ability to protect and repair age-induced cochlear mitochondrial DNA damage, thereby up-regulating mitochondrial function and improving energy-producing capabilities. [69]

A Stanford University study of patients with Alzheimer's disease found that acetyl-L-carnitine slowed the progression of the disease in younger subjects. [70]

The recommended dose of Acetyl-L-carnitine is 1,000 to 2,000 mg a day.

Coenzyme Q10

When coenzyme Q10 is orally administered, it is incorporated into the mitochondria of cells throughout the body where it facilitates and regulates the oxidation of fats and sugars into energy. Heart cells have a high energy demand, and initial clinical studies investigated the effect of Coenzyme Q10 on cardiac mitochondrial function. Therapeutic efficacy was shown in double-blind studies when CoQ10 was used in the treatment of congestive heart disease, coronary artery disease, and valvular disorders. Scientists are now looking at the effects of CoQ10 on another organ whose cells also require a high level of energy metabolism....the brain!

Here are the highlights from a study published in the Proceedings of the National Academy of Sciences [71]:

When coenzyme Q10 was administered to middle-age and old rats, the level of CoQ10 increased by 10% to 40% in the cerebral cortex region of the brain. This increase was sufficient to restore levels of CoQ10 to those seen in young animals.

After only two months of CoQ10 supplementation, mitochondrial energy expenditure in the brain increased by 29% compared to the group not getting CoQ10. The human equivalent dose of CoQ10 to achieve these results was 100-200 mg a day.

When a neurotoxin was administered, CoQ10 helped protect against damage to the striatal region of the brain where dopamine is produced.

When CoQ10 was administered to rats genetically bred to develop ALS (Lou Gehrig's disease), a significant increase in survival time was observed.

The conclusion by the scientists was: "CoQ10 can exert neuroprotective effects that might be useful in the treatment of neurodegenerative diseases."

This study showed that short-term supplementation with moderate amounts of CoQ10 produced profound anti-aging effects in the brain. Previous studies have shown that CoQ10 may protect the brain via several mechanisms including reduction in free radical generation and protection against glutamate-inducted excitotoxicity. This study documented that orally supplemented CoQ10 specifically enhanced metabolic energy levels of brain cells. While this effect in the brain has been previously postulated, the new study provides hard-core evidence.

Based on the types of brain cell injury that CoQ10 protected against, the scientists suggested that it may be useful in the prevention or treatment of Huntington's disease and Lou Gehrig's disease (amyotrophic lateral sclerosis). It was noted that while vitamin E delays the onset of Lou Gehrig's disease in mice, it does not increase survival time. CoQ10 was suggested as a more effective treatment strategy for neurodegenerative disease than vitamin E because survival time was increased in mice treated with CoQ10.

CoQ10 might be effective in the prevention and treatment of Parkinson's disease. A study showed that the brain cells of Parkinson's patients have a specific impairment that causes the disruption of healthy mitochondrial function. It is known that "mitochondrial disorder" causes cells in the substantia nigra region of the brain to malfunction and die, thus creating a shortage of dopamine. [72]

An interesting finding was that CoQ10 levels in Parkinson's patients were 35% lower than age-matched controls. This deficit of CoQ10 caused a significant reduction in the activity of enzyme complexes that are critical to the mitochondrial function of the brain cells affected by Parkinson's disease.

The ramifications of this study are significant. Parkinson's disease is becoming more prevalent as the human life-span is increased. This new study confirms previous studies that Parkinson's disease may be related to CoQ10 deficiency. The conclusion of the scientists was:

"The causes of Parkinson's disease are unknown. Evidence suggests that mitochondrial dysfunction and oxygen free radicals may be involved in its pathogenesis. The dual function of CoQ10 as a constituent of the mitochondrial electron transport chain and a potent antioxidant suggest that it has the potential to slow the progression of Parkinson's disease." (see Parkinson's protocol for more information)

CoQ10 levels decrease with aging. Depletion is caused by reduced synthesis of CoQ10 in the body along with increased oxidation of CoQ10 in the mitochondria. A CoQ10 deficit results in the inactivation of enzymes needed for mitochondrial energy production, whereas supplementation with CoQ10 preserves mitochondrial function.

Aged humans have only 50% of the CoQ10 compared to young adults, thus making CoQ10 one of the most important nutrients for people to supplement. CoQ10 is the most important supplement on this list to take on a daily basis. Thousands of published studies show that ginkgo, acetyl-L-carnitine, and CoQ10 play a critical role in brain cell energy metabolism, not only in healthy people, but also in those suffering from neurological diseases.

The recommended dose of CoQ10 is 100 to 300 mg a day.

Phosphatidylserine

Phosphatidylserine plays an important role in maintaining the integrity of brain cell membranes. The breakdown of brain cell membranes prevents glucose and other nutrients from entering the cell. By protecting the integrity of brain cell membranes, phosphatidylserine facilitates the efficient transport of energy-producing nutrients into cells, enhancing brain cell energy metabolism.

Abnormalities in the composition of phosphatidylserine have been found in patients with Alzheimer's disease. [73]

The recommended dose of phosphatidylserine (PS) is 100 to 300 mg a day.

Hormones

Hormones are required to facilitate brain cell energy, maintain proper levels of acetylcholine, and protect brain cell membrane function. These hormones help restore youthful synchronization of nerve impulses within the brain. Hormone supplementation is often required to achieve the requisite levels.

DHEA

Pregnenolone and DHEA improve brain cell activity and enhance memory. (Pregnenolone is converted into DHEA in the body.) DHEA is the most plentiful steroid hormone in the human body, but its exact function is unknown. What is known is that its concentration plummets with age: its daily production drops from 30 mg at age 20 to less than 6 mg at age 80. DHEA is naturally synthesized in abundance in young people from pregnenolone in the brain and the adrenal glands. It is known to affect the excitability of neurons in the hippocampus, the part of the brain responsible for memory.

Current findings suggest that DHEA enhances memory by facilitating the induction of neural plasticity, the condition that permits the neurons (nerve cells of the brain) to change in order to record new memories. Studies have shown that DHEA not only improves memory deficits, but also relieves depression in older people and increases perceived physical and psychological well-being. DHEA has been shown to help preserve youthful neurological function. Together, pregnenolone and DHEA help to maintain the brain cells' ability to store and retrieve information in short-term memory.

A recent study found that DHEA and 7-oxo-DHEA-acetate, which is formed from DHEA, completely reversed the memory deficit induced by an injection of scopolamine in young mice. Only 7-oxo-DHEA-acetate was effective, however, in similar tests on older mice. [74]

Pregnenolone

Pregnenolone initiates the memory storage process by stimulating the activity of an important molecule known as adenylate cyclase, which is needed to activate and regulate enzymes crucial to cellular energy production. Pregnenolone then regulates the sequential flow of calcium ions through the cell membrane. The pattern of calcium ion exchange may determine how memories are encoded by neurons. Pregnenolone also modulates chemical reactions, calcium-protein binding, gene activation, protein turnover, and enzymatic reactions involved in the storage and retrieval of memory.

An article published in the journal Brain Research found that pregnenolone sulfate increased acetylcholine release and enhanced spatial memory performance. Studies on rats showed that injections of pregnenolone into the brain caused a dose-dependant increase of acetylcholine output. The lower dose caused a short-term elevation (20 minutes) and the higher dose caused a long-term elevation (80 minutes). This study confirmed previous work suggesting that a modest increase in acetylcholine facilitates memory processes.   [75]

The suggested supplementation range for pregnenolone is 50 to 150 mg a day in three equal doses. The recommended dosage for DHEA is 25 to 50 mg a day. Women usually need less DHEA than men. Refer to the DHEA Replacement Therapy protocol before using pregnenolone or DHEA.

Melatonin

Melatonin, a naturally occurring hormone produced in the brain's pineal gland, also enhances cognitive function. It is one of the body's most potent natural antioxidants, making it ideal to prevent age-related dementias such as Alzheimer's disease that are thought to be caused, or at least exacerbated, by a lifetime of free-radical damage, especially since melatonin easily enters the brain from the bloodstream. Melatonin is also the primary regulator of brain cell synchronization, the body's internal clock, and is being researched as a possible treatment for various psychological conditions.

Abnormally low levels of melatonin have been discovered in patients suffering from some kinds of depression.

The suggested level of melatonin supplementation for enhancing neurological function in those over age 35 is 300 micrograms to 3 milligrams a night, one half hour before going to bed (melatonin has a sedative effect). Those over age 50 can take up to 6 milligrams before bedtime.

Estrogen

An article published in the journal Obstetrics and Gynecology evaluated 71 postmenopausal women, 28 of whom were taking estrogen hormone replacement therapy, relative to memory function. There was significantly better verbal memory function (paragraph recall) in those taking estrogen than those that were not.  [76]

A recent article published in the journal Brain Research described an experiment of mice whose ovaries were surgically removed. The administration of both 17 beta-estradiol and estrone improved retention in a test of foot-shock avoidance on a T-maze. Further, a low dose of 17 beta-estradiol reduced by at least tenfold the dose of either arecoline (a cholinergic agonist) or L-glutamate (a glutamatergic agonist) needed to improve retention. The authors concluded that these findings support the concept that estrogen improves memory by potentiating the activity of the cholinergic and glutamatergic systems. [77]

Testosterone

An article published in the journal Neurology described a randomized, double-blind, placebo-controlled study of 25 healthy volunteers aged 50 to 80 years. Participants received weekly intramuscular injections of either 100 mg testosterone enanthate or placebo (saline) for 6 weeks. Circulating total testosterone was raised an average of 130% from baseline at week 3 and 116% at week 6 in the treatment group. Estradiol increased an average of 77% at week 3 and 73% at week 6 in the treatment group. The treatment group had significant improvements in cognition for spatial memory (recall of a walking route), spatial ability (block construction), and verbal memory (recall of a short story) compared with baseline and the placebo group. The results suggest that short-term testosterone administration enhances cognitive function in healthy older men. [78]

Vitamins

Vitamins can protect and enhance cognitive function. B vitamins in particular play an integral role in the functioning of the nervous system and help the brain synthesize chemicals that affect moods. A balanced complex of the B vitamins is also essential for energy and for balancing hormone levels.

One recent study determined not only that low folate (a B vitamin) levels are associated with cognitive deficits, but also that patients treated with folic acid for 60 days showed a significant improvement in both memory and attention efficiency. [79]

In a 6-year study to determine the relationship between nutritional status and cognitive performance in 137 elderly people, several significant associations were observed between cognition and vitamin status. Higher present and past intake of vitamins A, C, E, and B complex were significantly related to better performance on abstraction and visuospatial tests. [80]

In addition to a direct effect, vitamins indirectly impact mental function by altering the levels of harmful or beneficial substances in the body. For instance, elevated homocysteine (an amino acid) levels have been linked to heart disease and poorer cognitive function. In one study, vitamin B6 and folate, taken at higher than recommended dosages, reduced blood levels of homocysteine.

Another study showed that less-than-optimal levels of vitamin B6, B12, and folic acid lead to a deficiency of S-adenosylmethionine (SAMe). SAMe deficiency can cause depression, dementia, or demyelinating myelopathy (a degeneration of the nerves). [81]

The typical American diet does not always provide these essential vitamins, at least in high doses. Because vitamin C and the B complex are water soluble and excreted from the body daily, they must be replenished daily. Older people are at greater risk for vitamin deficiency because they tend to eat less of a variety of foods, although their requirements for certain vitamins such as B6 are actually higher. Older people may also have problems with efficient nutrient absorption from food. Even healthy older people often exhibit deficiencies in vitamin B6, vitamin B12, and folate, as well as zinc.

Vitamin B6

An article published in the journal Psychopharmacology described a study of 76 elderly males given vitamin B6 versus placebo in relation to memory function. The authors conclude that vitamin B6 improves the storage and retrieval of information in the elderly patient. [82]

Vitamin B12

An article published in the Annals of Internal Medicine reviews vitamin B12 deficiency in the elderly population relative to memory impairment and neuropathy. The authors conclude that both memory problems and neuropathy have been treated successfully with vitamin B12 injections or supplementation. [83]

An article published in the New England Journal of Medicine reviewed subclinical vitamin B12 deficiency and the resulting neurological symptoms. The author states that many common difficulties, such as memory loss, muscle weakness and parasthesias might well be a product of vitamin B12 deficiency without accompanying macrocytosis or other clinical indicators. [84]

Methylcobalamin is a coenzyme form of vitamin B that has been identified to protect against neurological disease associated with aging.  The sublingual form of methylcobalamin is better absorbed since it does not become bound to food.  Because most sources of B12 are from protein (meat products), vegetarian diets may be lacking in this vitamin.   

Antioxidants

Free radicals are atoms or groups of atoms that can cause damage to cells by a process known as oxidation, which impairs the immune system and leads to infections and degenerative diseases. Free radicals occur as a result of air pollutants, smoke, radiation, environmental toxins, and processed foods, and are also released in the human body through sun exposure and stress. Antioxidants neutralize free radicals and help prevent such free-radical damage as normal brain aging. Their destructive activity has been implicated in many disease processes, including stroke and heart disease.

A recent study published in the prestigious Journal of the American Geriatric Society compared groups of older people over time and at a given moment with regard to antioxidant intake and memory performance. The study found that free recall, recognition, and vocabulary were significantly related to vitamin C and beta carotene levels. The levels of these antioxidants were found to be significant predictors of cognitive function even after adjusting for possible confounding variables such as differences in education, age, and gender. [85]

Vinpocetine.

Vinpocetine was introduced into clinical practice 22 years ago, in Hungary, for the treatment of cerebrovascular disorders and symptoms related to senility. Since then, it has been used increasingly throughout the world in the treatment of cognitive deficits related to normal aging. Vinpocetine is a pharmaceutical extraction from the periwinkle plant.

Cerebral Blood Flow

It is well established that normal aging results in a reduction of blood flow to the brain and a decrease in the metabolic activity of brain cells. Vinpocetine functions via several important mech­anisms to correct known multiple causes of brain aging. The biological actions of vinpocetine ini­tially showed that it enhances circulation and oxy­gen utilization in the brain, increases tolerance of the brain toward diminished blood flow, and inhib­its abnormal platelet aggregation that can inter­fere with circulation or cause a stroke.

Vinpocetine enhances cyclic GMP levels in the vascular smooth muscle, leading to reduced resis-tance of cerebral vessels and increased cerebral blood flow.

The effect of vinpocetine on memory functions was studied in 50 patients with disturbances of cerebral circulation. Improvement of cerebral cir­culation was observed after i.v. and oral adminis­tration of vinpocetine. Blood flow was most markedly increased in the gray matter of the brain. Improvement of memorizing capacity eval­uated by psychological tests was recorded after 1 month of vinpocetine treatment. Longer-term use was associated with alleviation or complete disap­pearance of symptoms of neurological deficit. No side effects attributable to the drug were observed. The doctors stated that vinpocetine is indicated in the treatment of ischemic disorders of the cerebral circulation, particularly in chronic vascular insufficiency. [86]

Electrical Activity

More recent studies demonstrate that vinpocetine offers significant and direct protection against neurological damage caused by aging. The molecular evidence indicates that the neuroprotec­tive action of vinpocetine is related to the ability to maintain brain cell electrical conductivity and to protect against damage caused by excessive intracellular release of calcium and sodium.  [87, 88]

In a study to ascertain how vinpocetine boosts cognition, scientists measured the electrical firing effects in the neurons of anesthetized rats. The administration of vinpocetine produced a signifi­cant increase in the firing rate of neurons. The sci­entists noted that the dose of vinpocetine used to increase electrical firing corresponded to the dose range that produced memory-enhancing effects. These results provided direct electrophysiological evidence that vinpocetine increases the activity of ascending noradrenergic pathways and that this effect can be related to the cognitive-enhancing characteristics of the compound. [89]

Beta-Amyloid

Vinpocetine has been shown to protect against oxidative damage from beta-amyloid, which may make it clinically useful for Alzheimer’s disease. [90]

Recent studies have suggested that the antioxidant effect of vinpocetine might contribute to the protective role exerted by the drug in reducing neuronal damage. [91]

Studies

In one double-blind clinical trial, vinpocetine was shown to effect significant improve­ment in elderly patients with chronic cerebral dysfunction. Forty-two patients received 10 mg of vinpocetine 3 times a day for 30 days, then 5 mg 3 times a day for 60 days. Placebo tablets were given to another 42 patients for the 90-day trial period. Patients on vinpocetine scored consistently better in all evaluations of the effectiveness of treatment, including measurements on the Clini­cal Global Impression (CGI) scale, the Sandoz Clinical Assessment–Geriatric (SCAG) scale, and the Mini-Mental Status Questionnaire (MMSQ). There were no serious side effects related to the treatment drug. [92]

In another double-blind study, 22 elderly patients with central nervous system degenerative disorders were treated with vinpocetine or placebo. Patients received 10 mg of vinpocetine 3 times a day for 30 days, then 5 mg 3 times a day for 60 days. Another 18 elderly patients were given matching placebo tablets for the 90-day trial. Vin­pocetine-treated patients scored consistently bet­ter in all evaluations of the effectiveness of treatment, including measurements on the CGI and SCAG scales, and the MMSQ. According to CGI assessments, severity of ill­ness decreased in 73% of the patients in the vinpocetine group at day 30 and in 77% of patients at day 90. Improvement was seen in 77% and 87% of the patients at days 30 and 90, respectively. Patients also showed statistically significant improvement for all SCAG items except one at days 30 and 90. The physician rated the improve­ment in 59% of the vinpocetine-treated patients as “good” to “excellent.” There were no serious side effects associated with the treatment drug. [93]

Vinpocetine safety and efficacy were demon­strated in a study of infants who suffered severe brain damage caused by birth trauma. Vinpocetine caused a significant reduction or disappear­ance of seizures. The vinpocetine group also showed a decrease of the phenomena of intracra­nial hypertension and normalization of psycho­motor development. [94]

The damaging effects of glutamate-induced excitotoxicity has been well established. A vitamin B12 metabolite called methylcobalamin has been shown to specifically protect against this type of neuronal injury. Vinpocetine has been documented to par­tially protect against excitotoxicity induced by a wide range of glutamate-related neurotoxins. [95, 96]

The benefits of vinpocetine are not restricted to the brain. One study showed beneficial effects in protecting the retina against uveretinal pathology caused by the hepatitis B virus. While hepatitis viruses primarily affect the liver, most people don't know that these viruses can also infect the heart muscle, retina, and other parts of the body. [97]

Another study showed that vinpocetine admin­istered to rats inhibited the development of gastric lesions induced by ethanol. Pretreatment with the non-steroidal anti-inflammatory drug indometha­cin counteracted the protective action of vinpocetine against ethanol-induced damage. This study showed that vinpocetine protected against a wide range of gastric insults and ulceration, indicating its potential clinical value as a gastroprotective agent. In Russia, vinpocetine is a popular drug used by alcoholics to recover from gastric and neu­rological ethanol-induced toxicity. [98]

Space motion sickness has been a perplexing problem in both the Soviet and U.S. manned space programs. Both the sensory conflict theory (neu­ronal signal mismatch) and the cephalic fluid shift concept explain the mechanism. Vinpocetine has been used successfully in offsetting space motion sickness in experimental test subjects. [99, 100]

Glutamine

Glutamine is considered a conditionally essential amino acid since it becomes essential during periods of excessive stress, such as in acute burns, inflammatory bowel disease or injuries. Glutamine is the preferred energy source for both the brain and the cells of the gastrointestinal tract. Glutamine may also be needed for memory.

A study found that methionine sulfoximine, a specific inhibitor of the enzyme glutamine synthetase, prevented consolidation of memory for a passive avoidance task in day-old chicks. Further the amnesia induced by methionine sulfoximine was successfully counteracted by L-glutamine and monosodium glutamate, and also by a cocktail of alpha-ketoglutarate and alanine.[101]

Tests of learning and memory in mice and rats (one-trial passive avoidance immediately followed by electroshock in mice and the pole-climbing test in rats) found a facilitating action for caffeine, L-glutamine and piracetam.  [102]

Conclusion

Age-associated mental impairment can range in severity from forgetfulness to senility to dementia. It can be caused by a wide variety of specific disease processes, many of which are treatable, or by life events, such as the loss of a loved one. It can also result from brain aging. Whatever its form or cause, it need not be accepted as a consequence of growing older.

Behavioral modifications, such as increased physical and mental activity and a healthy diet, can improve mental function both directly and indirectly by enhancing overall health. Memory can also be improved by using aids such as lists and routines, and by making connections to existing knowledge.

Age-associated mental impairment can be treated safely and effectively with memory- enhancing nutrients that increase available acetylcholine, brain cell energy boosters (including naturally occurring substances like acetyl-L-carnitine, ginkgo biloba extract, Coenzyme Q10, NADH, and phosphatidylserine, as well as FDA-approved and offshore drugs), hormones, and vitamins that become deficient (especially in older people), and antioxidants. It is advisable to consult your physician prior to any treatment program and to inform your physician of all supplements you take.

Postscript

There is currently much debate as to whether mild cognitive decline or memory problems are a risk factor for developing more serious neurological disease, such as dementia or Alzheimer’s disease. [103-109]

Perhaps the most important research paper published on age-associated memory impairment states that memory decline is not a normal feature of aging. What the researchers found was that in those people with mild memory impairment, memory loss tended to progress, whereas those people that were healthy did not experience memory impairment as they aged. [110]

Based on this debate, a separate protocol on Cognitive Enhancement was created that describes studies on supplements and drugs used to enhance mental performance in healthy people.

Summary

Recommendations

1.     Determine the severity and duration of the mental impairment and consult a physician if it interferes with daily functioning or has lasted a long time.

2.     Determine whether the mental impairment is the result of a specific disease process, which may be treatable, or life event, such as bereavement.

3.     Behavioral modifications, such as increased physical and mental activity and a healthy diet, may be helpful. Correct any hearing or vision deficits that interfere with activity.

4.     Utilize memory aids such as lists, routines, and actively making connections to existing knowledge.

Recommended Labs

The following lab tests may help determine the cause of the decline in memory and mental function and guide appropriate treatment:

·      A comprehensive hormone panel, including pregnenolone, DHEA, melatonin, estrogen, progesterone and testosterone levels may be useful in determining appropriate supplementation.

·      An essential fatty acid panel

·      Oxidative stress test

·      Vitamin B6 and B12 levels. Homocysteine levels should also be considered.

Supplements

1.     Choline (1,000 to 3,000 mg a day) or lecithin (10,000 mg a day), and/or phosphatidylcholine (100 to 600 mg a day).  Note: both choline and lecithin require the co-factors pantothenic acid (B5) (100 mg a day) and vitamin C (3000 to 6000 mg a day) to facilitate the conversion to acetylcholine.

2.     DHA (500-1,000 mg a day).  DHA can be found in Life Extension’s Super Max EPA (1,000 mg per tablespoon) and Mega EPA (300 mg per softgel). The recommended doses are 2 softgels daily of Mega EPA or 1 tablespoon daily of Super Max EPA.

3.     NADH (5 to 10 mg per day)

4.     Ginkgo biloba extract (120 mg a day)

5.     Acetyl-L-carnitine (1,000 to 2,000 mg a day)

 

6.     Coenzyme Q10 (100 to 200 mg a day).

7.     Phosphatidylserine (PS) (100 to 300 mg a day)

8.     Pregnenolone (50 mg per day). Refer to DHEA Replacement Therapy protocol before using pregnenolone.

9.     DHEA (25 to 50 mg a day). Refer to DHEA Replacement Therapy protocol before initiating DHEA or pregnenolone replacement.

10.  Melatonin (500 micrograms to 3 mg a night to maintain neurological function; 3 to 10 mg a night for those who have an age-related degenerative brain disease) one half hour before bedtime.

11.  Vitamins B6 and B12 (preferably in the form of methylcobalamin, 5 to 40 mg a day)

12.  Glutamine should be considered, especially if there is associated gastrointestinal problems.

13.  Estrogen and testosterone, if laboratory testing indicates a deficiency.

Innovative Drugs

Take one or a combination of the following drugs:

Picamilon (50 to 100 mg three times a day),

Pyritinol (200 mg three times a day)

Piracetam (2,400 to 4,800 mg a day)

Centrophenoxine (250 to 1,000 mg a day)

Hydergine (4 to 10 mg a day)

Deprenyl one 5 mg tablet two times per week

Nimodipine (30 mg three times a day). Take nimodipine under the care of a physician.

For more information.

Contact the National Institute on Aging, (800) 222-2225; the Alzheimer's Association, (800) 272-3900; and the National Institute of Neurological Disorders and Stroke, (800) 352-9424.

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