Medicine For People!

March 2007

For more than a year you've followed our in-depth orientation to the human brain. I've talked about the mechanisms of memory loss and dementia – what can go wrong and what we can do to keep our brains healthy. Last month I gave you a run-down of nutritional supplements I recommend as a regular regimen for preventing memory loss and dementia. This month I tie up the series by giving you the final information you need to make informed decisions about your own brain health.

First, I present an economic analysis, showing the costs of dementia and the costs of prevention. Not all nutritional supplements are reliable, so I'll give some brand names. Then, I'll talk about some medications your doctor may recommend for other problems, medications that, as a side effect, may prevent or slow the onset of dementia. If you have any of the problems I note, you'll want to read those sections. Finally, I conclude with the most important part – free medicine – lifestyle changes you can make to preserve brain function as you age.

Economic Analysis

After reading all the research and recommendations of this series on brain health, you may still be asking yourself what makes economic sense. Does the money you might shell out for supplements pay off in the long run?

Cost of dementia
First, let's see if we can estimate the cost of dementia. Estimations vary, but here are some factors to consider.

For all 65 year old men, 6 percent will develop Alzheimer's dementia specifically, and 11 percent will develop dementia of some form over their remaining lifetime. For all 65 year old women, the risks are 12 percent for Alzheimer's dementia and 19 percent for any dementia.1 2 Added up, the numbers suffering from dementia are huge. According to the Alzheimer's Health Assistance Foundation,

More than 4.5 million Americans are believed to have Alzheimer's disease and by 2050, the number could increase to 13.2 million. Approximately 59,000 victims die and 350,000 new cases of Alzheimer's disease are diagnosed each year. America is not alone in dealing with this terrible affliction. In every nation where life expectancy has increased, so has the incidence of Alzheimer's disease. Alzheimer's disease is becoming tragically common. It is estimated that there are currently 18 million people worldwide with Alzheimer's disease. This figure is projected to nearly double by 2025 to 34 million people.3

If we could delay the onset of dementia by two years, after 50 years there would be 2,000,000 fewer cases in the US than currently projected.4

Now let's look at the economics. Considering Alzheimer's dementia only, again from the Alzheimer's Health Assistance Foundation,

In terms of health care expenses and lost wages of both patients and their caregivers, the cost of Alzheimer's disease nationwide is a staggering $80 to $100 billion per year. The yearly cost of caring for one Alzheimer's patient is $18,400 for mild symptoms, $30,100 for moderate symptoms, and $36,132 for advanced symptoms. The average direct cost of caring for an Alzheimer's patient from diagnosis to death is $174,000. The average annual cost for an assisted living facility is $34,860, and the average daily cost of a private room in a nursing home is $203, which calculates to $74,095 per year.

These are just the monetary costs. No one can put a dollar figure on the suffering of the individuals involved, the loss of the impaired individual's contribution to our world, and the work and anxiety experienced by their families.

Cost of Preventive Supplements
Now let's look at the costs of supplements that delay dementia.

I've set out two options here. First is the lower cost option. These supplements have passed tests by ConsumerLab.com, but not all meet the highest standards of quality.

Lower Cost Option
Manufacturer Substance Daily cost
Thorne multivitamin BN 5 3 capsules twice daily $0.96
Vitamin World lipoic acid 100 mg 1 capsule daily $0.15
Vitamin World Acetyl-L-carnitine 500 mg daily $0.61
Vitamin World phosphatidyl-serine 1 capsule twice daily $0.38
Carlson Cod liver oil 2 teaspoons daily $0.70
Daily cost   $2.48
Monthly cost   $74

Here follow the premium manufacturers.

Higher Cost Option
Manufacturer Substance Daily cost
Thorne multivitamin BN 5 3 capsules twice daily $0.96
Thorne Neurochondria 1 capsule twice daily $1.20
Carlson Cod liver oil 2 teaspoons daily $0.70
Daily cost   $2.86
Monthly cost   $86

Neurochondria at 2 capsules per day contains 200 milligrams acetyl-L-carnitine, 200 milligrams phosphatidyl-serine, 100 milligrams of coEnzyme Q10, more biologically active forms of vitamin B12 and folic acid, 100 milligrams of the intracellular antioxidant glutathione, and 80 milligrams of r-lipoic acid, a more active form of lipoic acid. Otherwise, except for manufacturing practices, quality of raw materials, and additives, the options are equivalent in label dose of active ingredient. Costs do not include taxes or shipping. Volume discounts are available for both options.5

In case you're wondering about my own economic interest, let me remind you that our clinic's nutritional dispensary is run on a non-profit basis. We price our nutritional supplements at a slim margin to cover our costs. Any profits that remain at the end of the year, we donate to the United Good Neighbors Fund.

My name, Rienstra, is of Dutch origin, and the Dutch carry a reputation for thrift. (Typical Dutch joke: a guy drops in to his friend's apartment, to find him pulling down his wallpaper. "Redecorating?" "No. Moving.") Next month we'll discuss quality control of nutritional products, and you'll learn why the lowest price isn't always the best buy.

I have spent many hours on the telephone with supplement vendors, many hours quizzing sales reps, researching claims, once driving a few hours to tour a plant. There are better and worse ways to produce these products, as we will discuss in next month's newsletter. The old joke about the making of laws and sausage applies to supplements as well.

In addition to the dementia-preventive effect of this regimen, both of these options provide generous anti-oxidant protection against heart disease and stroke (fish oils, lipoic acid, and B vitamins), osteoporosis and prostate/cervical/breast cancer (1000 units vitamin D, selenium, folic acid), and ample multiple vitamin/mineral supplementation.

What Benefit Can One Reasonably Expect
We all know someone who is an exception to the rule, such as a smoker who lived almost forever or a vegan who died at age 50. Certainty is a chimera. But there is a law of averages. Let's look at how it applies to dementia.

We've discussed all these studies previously, so I just list the a few of the conclusions here with the details in a footnote.

People taking vitamin E alone developed Alzheimer's at only 30 percent of the normal rate.6

People with dementia taking high quality ginkgo alone, experienced a two year extension of independent living.7

Elderly people taking a multiple vitamin experienced improved memory and cognition after a year, while a placebo group did not improve.8

These are just a few of the studies that have convinced me that nutritional supplements promote brain health. For more details, review previous issues of this newsletter.

The most conservative way to analyze the economics is to look at the remaining lifetime risk for a 65 year old. When we consider that a 65 year old woman has a 19 percent chance of developing some type of dementia in her remaining lifetime, should that happen she will incur $30,000 in expense per year or $174,000 total. Were she to delay that dementia for two years, she would save about $60,000. That is the cost of 60 years of the supplements listed above. Of course, there's an 81 percent chance she won't develop dementia. In that case she will profit only if the supplement program provides health benefits in some other way. Based in my research quoted in this series, I believe the supplements also give her a better chance of preserving word recall and cognitive thinking, good heart health and bone strength.

The economic analysis is slightly less compelling for a 65 year old male with his 11 percent remaining lifetime risk of dementia.

Click here for an estimate of how long you have left.

My own bet is that this regimen will delay dementia for longer than the two years already demonstrated. So far, studies on phosphatidyl-serine, acetyl-L-carnitine and other substances mentioned have demonstrated cognitive improvement, but no one has specifically looked at populations to see if the rate of dementia is reduced. People with higher levels of folic acid developed dementia at about a third the rate of those with the lowest levels over a period of just four years. We've no direct proof that supplemental folic acid will accomplish the same thing, but I think it is a reasonable assumption. You can check back and reread details of the series to reach your own conclusions on these assumptions.

Over time, researchers will look at all these issues. We can wait the decade or more that will require, but the sand is running through the glass today.

Many people tell me "I just don't like to take a bunch of capsules and supplements." This is one reason we have gone into such detail in this series. If you are one of those individuals, you can read through our information again and choose those specific supplements that seem most reasonable to you. And whatever your choice about supplements, read on. You'll learn that you have the ability to eat, sleep, live, and exercise in a way that powerfully promotes brain health.

Measures to Take for Special Problems

First, however, let's note that some treatments for medical problems have the side-effect of improving cognition. Let's review them by category.

Problem: Hormone Deficiency

DHEA - Dehydroepiandrosterone

DHEA gets some press as being of benefit for aging disorders. Studies on DHEA for cognitive disorders have shown a benefit only for people with low levels of DHEA, especially women. Take DHEA only if your doctor believes you are deficient, or if you require it for some other purpose.

Testosterone

There is evidence that some men with cognitive decline will respond to testosterone replacement.9 Since testosterone deficiency in men can lead to depression, cognitive improvement may be due either to relief of depression or an effect on the brain. Testosterone replacement may have some adverse consequences as does estrogen replacement and is best avoided if possible.

So, Guys! Don't think you can eat junk and watch TV and rescue yourself with testosterone when the lights start to go out. Exercise! Eat well! Use your head!

Estrogen

In the laboratory, estrogen benefits brain structure and function in about a dozen different ways.10 Women in the throes of menopause think better, on average, when taking supplemental estrogen. However, once the brain cells are in trouble, estrogen doesn't help.11 Studies of estrogen in older women have shown, in fact, a hastening of neurodegeneration.12

Thyroid hormone

Hypothyroidism impairs mental function and sometimes occurs in a "subclinical" form that doesn't show up on the standard tests. If you have depression or cognitive difficulties, make sure your doctor considers a trial of thyroid hormone.

Problem: Poor Sleep

Poor sleep is a major risk factor for cognitive decline, as it activates the stress response and promotes vascular disease.

Melatonin

The brain produces the hormone melatonin at night. Melatonin helps reduce the risk of cancer. Melatonin production falls as we age13 In several small studies, melatonin improved cognition in both healthy14 and demented15 individuals. It should be most effective in those people who sleep better as a result, but its effect is not dependent upon sleep. Take melatonin only if needed for sleep. And if you still can't sleep, get some professional help.

Problem: Poor Memory

Now that we've outlined most of the major physiologic issues of Alzheimer's dementia and brain aging, let's pay a visit to some nutrients that have been studied for their effect on mental function, and specifically on amyloid plaque, neurofibrillary tangles, and acetylcholine.

Citocholine

Citocholine, also known as CDP-choline and cytidine-5-diphosphocholine, provides raw materials for acetylcholine, the neurotransmitter most severely affected by Alzheimer's dementia, as well as for phosphatidylcholine and sphingomyelin, both major constituents of cell membranes. Although we produce citocholine on our own, it is well-absorbed by mouth and readily crosses the blood brain barrier. Supplemental citocholine appears to

  • increase our ability to repair damaged cell membranes in the brain;
  • increase levels of acetylcholine and other neurotransmitters;
  • decrease the tendency of damaged neurons to form amyloid plaque.

Most of the above has been learned from animal studies. In humans, researchers have put most of their attention on people with stroke. One study of 272 people with stroke showed that half of a citocholine treated group had improved by two weeks, compared with 30 percent of a placebo group.16 However, three other studies at Oregon Health Sciences University showed less convincing benefit.17

Several small studies followed people with age-associated memory impairment, showing a modest benefit.18 Studies on Alzheimer's dementia have showed but slight benefit.

Citocholine appears to cause infrequent side-effects, usually headache or GI upset. Research continues. I don't recommend it. There are too many more effective agents.

Huperzine A
Extracted from a club moss, Huperzia serrata, huperzine A improved memory and daily function in people with Alzheimer's dementia in two Chinese studies. Among its several mechanisms of action, it influences acetylcholine, a neurotransmitter reduced in Alzheimer's dementia and improved by the pharmaceuticals Tacrine and Aricept. I recommend this only for those who have memory problems unresponsive to other measures, or if it is contained in another supplement you take for more pressing reasons.19

Bacopa

Bacopa monniera has been used in Ayurvedic medicine for centuries to enhance mental function. When given to children, memory and learning is enhanced. In adults anxiety is diminished and concentration and memory improved.20 I recommend this only for those who have memory problems or if it is contained in another supplement you take for more pressing reasons.

Problem: Vascular Disease

Statin drugs

These not only reduce cholesterol but also have an anti-inflammatory effect. This anti-inflammatory effect protects the heart. What is less well known is that it protects the brain as well, and statin users show less cognitive decline than controls.21 Take a statin only if you have vascular disease.

Coenzyme Q10

CoQ10 is required for mitochondrial function; levels fall in those taking statins. If you are taking a statin drug, take at least 30 mg of coQ10 daily.

Problem: Arthritis

NSAIDS

The non-steroidal anti-inflammatory agents (such as aspirin, naproxen and ibuprofen) reduce microinflammation, so we would expect them to have a dementia-slowing effect, and in fact they have. Several studies show that people who take NSAIDS get less dementia.22 However, since they have a number of adverse effects, including GI bleeding, fluid retention, and others, take NSAIDs only if required for other reasons.

Problem: Hearing Loss

Every ear, nose, and throat doctor knows that we humans do not easily tolerate the social isolation brought about by poor hearing. When hearing is poor, often we will "hear" things that do not really exist. And when hearing is very poor in one ear, the risk of dementia is six times normal; with poor hearing in both ears, twelve times normal.23 And why not? We know that mental stimulation is one requirement for maintenance of optimal mental function. Therefore, if you find you are having difficulty understanding those around you, take advantage of modern technology: get an audio system onto your ear! If you are worried how it will look, ask for one in some shiny color and brag about your new Bluetooth headset!

Free Medicine!

You now know the cost of brain protecting supplements, but lifestyle change should give you as much or more benefit, and cost you $0. Imagine the savings over a lifetime! The following practices will help keep you healthy and protect your brain.

Don't smoke
Cigarette smoke and many other pollutants increase the microinflammatory response, not just in the blood vessels but in the brain substance as well. Smokers are over three times as likely to develop dementia as are non-smokers or former smokers.24 If you still smoke, stop.

Eat Your Veggies
In October of 2006, researchers at the Rush Institute for Healthy Aging in Chicago studied 3700 people over 64 years old for a period of six years. Cognitive loss was reduced by 40 percent in those who consumed three or more servings of vegetables a day, compared to those who consumed one serving a day.25 Green leafy vegetables seemed to be most protective.

Evidence is overwhelming that the micronutrients in our food reduce the inflammatory background signals in our body, including our brains. This is one reason why study after study shows that various micronutrients reduce our likelihood of developing dementia. Flavonoids in foods, for example, inhibit inflammatory enzymes and prevent oxidative damage to blood vessels and to specific structures in the brain. Of the some 5000 flavonoids in nature, we know of the biologic functions of just a few, but they are generally vital to our health. Many of these flavonoids give color to plants, as in carrots, spinach leaves, peppers, tomatoes, and the red tint at the base of spinach stems. Give yourself a variety of colors on your plate!

Avoid Junk Food
Sugars are a major contributor to microinflammation. Sugars are also calming. Find some other way to bring yourself peace. If you are motivated to improve your diet, and wish to follow your progress, ask us for a hemoglobin A1c blood test. Lower levels of hemoglobin A1c indicate reduced risk to health from sugar in the diet.

Spend Your Money on Quality Comestibles!
Healthy food can cost more than meat and potatoes. You cannot skimp by buying low-quality food and count on a medical miracle to repair the damage. And if it does, it is going to cost much more than your grocery savings.

Rein in the Weight
Evidence is overwhelming that obesity increases the inflammatory background signals in our body, including our brains. Fat cells produce many inflammatory substances. This is one reason why study after study shows that people with excess weight develop dementia more often.

Go to Bed on Time
Evidence is overwhelming that adequate sleep reduces the inflammatory background signals in our bodies, including our brains. This is one reason why study after study shows that people who sleep well develop dementia less often.

Think About Coffee and Alcohol
Coffee raises homocysteine but lowers the risk of Parkinson's disease and diabetes. Light-to-moderate alcohol intake lowers homocysteine and seems to protect the brain from vascular damage26 but continues to ruin many lives. If you drink either beverage, be moderate. If moderation isn't an option, quit.

Respect the Egg
Eggs contain choline, another B vitamin, which importantly supports healthy membranes in the brain. Choline changes into betaine, which helps recycle homocysteine into methionine. Lest you worry about cholesterol, remember that your liver makes four to eight eggs worth of cholesterol a day, so for most people, cholesterol in their diet is not the problem. Studies show that two eggs a day will not increase cholesterol in the great majority of people.

Put your Mind to Use
Use it or lose it. Many studies indicate that the brain wears out faster when we don't use it. Simply put, people with more education and more mental activity develop dementia less often.27

Physical Exercise
In previous newsletters, we have noted that exercise protects the brain by

  • slowing aging of the blood vessels which feed the brain
  • reducing the microinflammation that hastens brain cell destruction as we age
  • stimulating growth of new neurons
  • reducing the accumulation of fat cells that produce inflammatory molecules that age the brain
  • preventing elevated glucose levels that trigger signals for cell destruction in the brain
  • reducing homocysteine.

(Enough reasons for ya?)

Men (but not women, according to one study) are more likely to develop Alzheimer's dementia when they have high blood pressure or are obese, and most likely if they are both.28 Exercise reduces blood pressure and weight.

But, you may rightfully object, all those things are just theoretical. Does exercise really make a difference? Below are the results of a study done at Group Health and the VA Health Care System in Seattle. Researchers recruited about 1700 people over age 65 who were in the higher seventy-five percent of the population for mental function. They did not enroll those who scored less well on intelligence tests because such folks are already at higher risk for dementia. Then they observed these individuals for about six years and counted how many developed dementia.

Figure 3

Figure 329

This graph shows that at any age, people who exercised three or more times per week were more likely to be free of dementia than those who exercised less. The top line are the regular exercisers, who developed dementia at a rate of 13 people per 1000 person-years, compared to a rate of about 20 for infrequent exercisers..

For you couch-potatoes, here's some good news.

Figure 4

Figure 430

This graph tracks the progress of the couch potatoes. These were folks who scored most poorly on fitness. What you see is that among these sofa lovers, those who took a break for exercise three times a week showed a great benefit compared to those who stayed on the sofa. So, if you're not running marathons, if you're not running at all, in fact, you stand to gain the most31. Look at yourself in that mirror and smile!

By the way, studies have shown that physical conditioning programs improve memory and cognitive functions, as well as slowing brain tissue loss in areas of the brain most affected by Alzheimer's dementia. Indeed, one study showed that even after people had developed Alzheimer's dementia, they maintained function better when they exercised.32

So turn that TV off! Engage your mind with the world around you! Exercise!

Listen to Your Doctor!

High blood pressure, diabetes, vascular disease are just three of many conditions that increase the risk of dementia. Trust that your doctor doesn't mind hard questions about what is best for you individually, and recognize that he or she very much wants to help you maintain your health as long as possible.

 

Summary
We are programmed to degenerate and die. What amazes me is how long and how well we last given how terribly many of us take care of ourselves. Animals in most species die very quickly given our diet and stress level.

Protective mechanisms delay our decline. Optimal nutrition allows these protective mechanisms to operate as effectively and as long as possible. Over the course of these 12 articles, we've surveyed that miraculous electrochemical engine inside our skulls. Now you are on your own. It is my wish that the coming years will bring you health, vigor, and brain power to live a full, productive, and interesting life, a life you can be proud of.

 


Endnotes:

1 Lifetime risk of dementia and Alzheimer's disease. The impact of mortality on risk estimates in the Framingham Study. Neurology 1997 Dec;49(6):1498-504

We estimated the remaining lifetime risks of developing Alzheimer's disease (AD) and dementia from all causes, based on data from longitudinal population studies. The risk of developing AD during one's lifetime depends on both disease incidence and life expectancy. Conventional estimates of cumulative incidence overestimate the risk when there is a substantial probability of mortality due to competing causes. A total of 2,611 cognitively intact subjects (1,061 men, 1,550 women; mean age, 66 +/- 7 years) were prospectively evaluated for the development of AD or other dementia. A modified survival analysis was used to estimate both cumulative incidence and the sex-specific remaining lifetime risk estimates for quinquennial [five year] age groups above age 65 years. Over a 20-year follow-up period, 198 subjects developed dementia (120 with AD). The remaining lifetime risk of AD or other dementia depended on sex, being higher in women, but varied little with age between 65 and 80 years. In a 65-year-old man, the remaining lifetime risk of AD was 6.3% (95% CI, 3.9 to 8.7) and the remaining lifetime risk of developing any dementing illness was 10.9% (95% CI, 8.0 to 13.8); corresponding risks for a 65-year-old woman were 12% (95% CI, 9.2 to 14.8) and 19% (95% CI, 17.2 to 22.5). The cumulative incidence between age 65 and 100 years was much higher: for AD, 25.5% in men and 28.1% in women; for dementia, 32.8% in men and 45% in women. The actual remaining lifetime risk of AD or dementia varies with age, sex, and life expectancy and is lower than the hypothetical risk estimated by a cumulative incidence in the same population.

2 Age-specific incidence rates of Alzheimer's disease: the Baltimore Longitudinal Study of Aging. Neurology 2000 Jun 13;54(11):2072-7

OBJECTIVE: To estimate age-specific incidence rates of AD in the Baltimore Longitudinal Study of Aging (BLSA). BACKGROUND: The BLSA is a volunteer cohort of normal subjects followed longitudinally with biennial evaluations at the Gerontology Research Center of the National Institute on Aging. METHODS: Subjects are 1236 participants (802 men, 434 women) in the BLSA with longitudinal follow-up between January 1985 and May 1998. The average length of follow-up was 7.5 years, with participants evaluated every 2 years by physical, neurologic, and neuropsychological examinations. Using Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., revised and National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria, the authors diagnosed dementia and AD. RESULTS: The authors diagnosed 155 cases of dementia, of which 114 (74%) were AD. Incidence rates of AD increased with age from an estimated 0.08% per year (95% CI 0.00 to 0.43) in the 60 to 65 age group to an estimated 6.48% per year (95% CI 5.01 to 8.38) in the 85+ age group for men and women combined. The doubling time of incidence rates was estimated to be approximately 4.4 years and the median time of conversion from mild cognitive impairment to diagnosis of AD was estimated to be 4.4 years. There was a trend for women to have higher incidence rates than men and for fewer years of education to be associated with higher incidence rates; however, these effects were not significant. CONCLUSION: Incidence rates for AD in the BLSA are consistent with published rates in other studies. The longitudinally followed subjects of the BLSA offer a unique opportunity to prospectively investigate the antecedents of AD.

4 Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am J Public Health 1998 Sep;88(9):1337-42

OBJECTIVES: The goal of this study was to project the future prevalence and incidence of Alzheimer's disease in the United States and the potential impact of interventions to delay disease onset. METHODS: The numbers of individuals in the United States with Alzheimer's disease and the numbers of newly diagnosed cases that can be expected over the next 50 years were estimated from a model that used age-specific incidence rates summarized from several epidemiological studies, US mortality rates, and US Bureau of the Census projections. RESULTS: in 1997, the prevalence of Alzheimer's disease in the United States was 2.32 million (range: 1.09 to 4.58 million); of these individuals, 68% were female. It is projected that the prevalence will nearly quadruple in the next 50 years, by which time approximately 1 in 45 Americans will be afflicted with the disease. Currently, the annual number of new incident cases in 360,000. If interventions could delay onset of the disease by 2 years, after 50 years there would be nearly 2 million fewer cases than projected; if onset could be delayed by 1 year, there would be nearly 800,000 fewer prevalent cases. CONCLUSIONS: As the US population ages, Alzheimer's disease will become an enormous public health problem. interventions that could delay disease onset even modestly would have a major ublic health impact.

5 We give our patients a 15% volume discount on all sales over $100, with higher discounts for larger purchases..

6 Morris MC,Evans DA,Bienias JL,Tangney CC,Bennett DA,Aggarwal N,Wilson RS,Scherr PA,others. "Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study." Journal of the American Medical Association. 2002 Jun 26;287:3230-7. (Issue number 24) Research reported by Rush Institute for Healthy Aging, Rush-Presbyterian-St Luke's Medical Center, 1645 W Jackson, Suite 675, Chicago, IL 60612, USA. mmorris@rush.edu. =18976= = Conclusion: This study suggests that vitamin E from food, but not other antioxidants, may be associated with a reduced risk of AD. Unexpectedly, this association was observed only among individuals without the APOE epsilon 4 allele. = Author's abstract: CONTEXT: Oxidative processes have been suggested as elements in the development of Alzheimer disease (AD), but whether dietary intake of vitamin E and other antioxidant nutrients prevents its development is unknown. OBJECTIVE: To examine whether intake of antioxidant nutrients, vitamin E, vitamin C, and beta carotene is associated with incident AD. DESIGN, SETTING, AND PARTICIPANTS: Prospective study, conducted from 1993 to 2000, of individuals selected in a stratified random sample of community-dwelling residents. The 815 residents 65 years and older were free of AD at baseline and were followed up for a mean of 3.9 years. They completed food frequency questionnaires an average of 1.7 years after baseline. MAIN OUTCOME MEASURE: Incident AD diagnosed in clinical evaluations with standardized criteria. RESULTS: Increasing vitamin E intake from foods was associated with decreased risk of developing AD after adjustment for age, education, sex, race, APOE epsilon 4, and length of follow-up. Relative risks (95% confidence intervals [CIs]) from lowest to highest quintiles of intake were 1.00, 0.71 (0.24-2.07), 0.62 (0.26-1.45), 0.71 (0.27-1.88), and 0.30 (0.10-0.92) (P for trend =.05). The protective association of vitamin E was observed only among persons who were APOE epsilon 4 negative. Adjustment for other dietary factors reduced the protective association. After adjustment for baseline memory score, the risk was 0.36 (95% CI, 0.11-1.17). Intake of vitamin C, beta carotene, and vitamin E from supplements was not significantly associated with risk of AD.

7 [Delay in progression of dependency and need of care of dementia patients treated with Ginkgo special extract EGb 761]
Wien Med Wochenschr. 2004 Nov;154(21-22):511-4.

In studies on the efficacy of antidementia drugs, a delay in symptom progression was often postulated based on a comparison of the change upon treatment and an assumed "natural" progression. Such comparisons were usually based on the cognitive subscore of the Alzheimer's Disease Assessment Scale (ADAS-cog), using either the drug-placebo differences after randomized treatment or the changes upon active drug treatment in open-label extension studies. Considering quality of life, competence, cost of care, and economics of therapeutic measures, a delay in the progression of dependency and need of care appears to be more relevant than a delay in cognitive abilities not directly related to activities of daily living. Therefore, for dementia patients treated with the Ginkgo special extract EGb 761, the delay in loss of capacities needed to cope with the demands of daily living was estimated, based on the Geriatric Evaluation of Relative's Rating Instrument (GERRI). The drug-placebo differences documented after 26 and 52 weeks of treatment corresponded to a delay in progression by 10 and 21 months, respectively. Regarding the subgroup with dementia of the Alzheimer type, the estimated delay was 16 and 25 months, respectively. It could thus be shown that by treatment with EGb 761 the progression of dependency and need of care can be slowed down, which may have an impact on costs for care, e.g. by delaying nursing home placement.

8 "Effect of Vitamin and Trace-Element Supplementation on Cognitive Function in Elderly Subjects" Chandra RK Nutrition 2001 17:709

9 Increasing testosterone levels and effects on cognitive functions in elderly men and women: a review. Curr Drug Targets CNS Neurol Disord 2005 Oct;4(5):531-40
Oxford Project To Investigate Memory and Ageing & Department of Human Sciences, Loughborough University, UK.

Low testosterone (T) levels may predispose to Alzheimer disease (AD), but it is unclear whether this is a co-morbid effect due to cachexia, subclinical hyperthyroidism or other co-morbidity. The biological plausibility for potential protective effects of T on brain functions is substantial. In addition, higher levels of gonadotropins found in older cases with AD suggest that low levels of T are not due to brain degeneration and that the hypothalamic-pituitary-gonadal (HPG) axis is still intact. Men genetically at risk for AD were also already found to have lower levels of T. However, despite having lower levels of T, women do not show accelerated cognitive decline with age when compared to men. In addition, castration has not necessarily shown a decline in cognitive functions; some studies even found improvement of memory recall. Age may be an important factor when assessing optimal levels of T and several studies suggest that free or bioavailable T may be a better marker than total T levels when investigating associations of androgen activity with cognitive function. Small-scale T intervention trials in elderly men with and without dementia suggest that some cognitive deficits may be reversed, at least in part, by short term T supplementation. Age and prior hypogonadism may play an important role in therapy success and these factors should be investigated in more detail in future large scale randomized controlled studies. For elderly women, T treatment does not seem to have additional benefits over estrogen treatment for postmenopausal complaints and cognitive decline and may increase cardiovascular disease.

10 Estrogen and cognition, with a focus on Alzheimer's disease. Semin Reprod Med 2005 May;23(2):172-9

Cognitive aging is associated with decreases in memory, attention, and visual/motor performance and skills. Dementia consists of loss of memory and other cognitive abilities, associated with social or occupational impairment. Potential neuroprotective effects of estrogen include lowering beta-amyloid, enhancing cholinergic function, promoting synaptic plasticity and nerve process growth, reducing oxidative stress, and enhancing brain glucose transport. Observational and longitudinal studies suggest that hormone therapy may attenuate age-associated cognitive impairment or decrease Alzheimer's disease but this has not been confirmed by randomized clinical trials. A critical window of time may exist around the menopause when hormone therapy may delay or decrease cognitive changes; however, hormone therapy initiated in the late postmenopause does not improve global cognition and may increase dementia risk.

11Investigative models for determining hormone therapy-induced outcomes in brain: evidence in support of a healthy cell bias of estrogen action. Ann N Y Acad Sci 2005 Jun;1052:57-74
Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90089-9121, USA.

The profound disparities between the largely positive basic science findings of gonadal steroid action in brain and the adverse outcomes of recent hormone therapy clinical trials in women who are either aged postmenopausal or postmenopausal with Alzheimer's disease have led to an intense reassessment of gonadal hormone action and the model systems used in basic and clinical science. The power of model systems is their predictive validity for a target population--in this case, menopausal women considering the health benefits and risks of hormone therapy. Analysis of the model systems used across the basic to clinical research continuum separate into two broad classes: those that use prevention interventions in healthy organisms and those that use hormone interventions in organisms with compromised neurological function. Basic science analyses that led to elucidation of the neurotrophic and neuroprotective effects of estrogen and the underlying mechanisms of action typically used a prevention-based experimental paradigm. This paradigm relies on healthy neurons/brains/animals/humans as the starting foundation followed by exposure to estrogen/hormone followed by exposure to neurodegenerative insult. The prevention paradigm in basic science analyses parallels the analyses of Sherwin and colleagues (Psychoneuroendocrinology 13: 345-357, 1988), who investigated the cognitive impact of estrogen therapy in women with surgical- or pharmacological-induced menopause. Observational retrospective and prospective studies are also consistent with the healthy cell bias of estrogen action and a prevention paradigm of estrogen or hormone therapy intervention. For the most part, the epidemiological observational data indicate reduction in the risk of Alzheimer's disease in women who began estrogen or hormone therapy at the time of the menopause. In contrast, studies that fall within the second class, hormone intervention in organisms with compromised neurological function--that is, a treatment paradigm--exhibit a mixed profile. In a randomized double-blind clinical trial of estrogen therapy in a cohort of women aged 72 or more years and diagnosed with Alzheimer's disease, estrogen therapy resulted in a modest benefit in the short term (2 months) and adverse progression of disease in the long term (12 months). In the Women's Health Initiative Memory Study (WHIMS) cohort of women 65 or more years of age, with no indicators of neurological disease but with variable health status, estrogen and hormone therapy for 5 years increased the risk of developing Alzheimer's disease. These data would suggest that as the continuum of neurological health progresses from healthy to unhealthy, so too do the benefits of estrogen or hormone therapy. If neurons are healthy at the time of estrogen exposure, their response to estrogen is beneficial for both neurological function and survival. In contrast, if neurological health is compromised, estrogen exposure over time exacerbates neurological demise. Based on these and other data, a hypothesis of a healthy cell bias of gonadal hormone action is put forth. The healthy cell bias of estrogen action hypothesis provides a lens through which to assess the disparities in outcomes across the domains of scientific inquiry and to access future applications of estrogen and hormone therapeutic interventions.

12 Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study. JAMA 2004 Jun 23;291(24):2959-68

CONTEXT: The Women's Health Initiative Memory Study (WHIMS) previously reported that estrogen plus progestin therapy does not protect cognition among women aged 65 years or older. The effect of estrogen-alone therapy, also evaluated in WHIMS, on cognition has not been established for this population. OBJECTIVES: To determine whether conjugated equine estrogen (CEE) alters global cognitive function in older women and to compare its effect with CEE plus medroxyprogesterone acetate (CEE plus MPA). DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled ancillary study of the Women's Health Initiative (WHI), WHIMS evaluated the effect of CEE on incidence of probable dementia among community-dwelling women aged 65 to 79 years with prior hysterectomy from 39 US academic centers that started in June 1995. Of 3200 eligible women free of probable dementia enrolled in the WHI, 2947 (92.1%) were enrolled in WHIMS. Analyses were conducted on the 2808 women (95.3%) with a baseline and at least 1 follow-up measure of global cognitive function before the trial's termination on February 29, 2004. INTERVENTIONS: Participants received 1 daily tablet containing either 0.625 mg of CEE (n = 1387) or matching placebo (n = 1421). MAIN OUTCOME MEASURE: Global cognitive function measured annually with the Modified Mini-Mental State Examination (3MSE). RESULTS: During a mean follow-up of 5.4 years, mean (SE) 3MSE scores were 0.26 (0.13) units lower than among women assigned to CEE compared with placebo (P =.04). For pooled hormone therapy (CEE combined with CEE plus MPA), the mean (SE) decrease was 0.21 (0.08; P =.006). Removing women with dementia, mild cognitive impairment, or stroke from the analyses lessened these differences. The adverse effect of hormone therapy was more pronounced among women with lower cognitive function at baseline (all P<.01). For women assigned to CEE compared with placebo, the relative risk of having a 10-unit decrease in 3MSE scores (>2 SDs) was estimated to be 1.47 (95% confidence interval, 1.04-2.07). CONCLUSION: For women aged 65 years or older, hormone therapy had an adverse effect on cognition, which was greater among women with lower cognitive function at initiation of treatment.

13 Reiter, RJ Oxidative processes and antioxidant defense mechanisms in the aging brain. FASEB J. 1995 9:526.

14 Cognitive effects of exogenous melatonin administration in elderly persons: a pilot study. Am J Geriatr Psychiatry 2004 Jul-Aug;12(4):432-6

OBJECTIVE: Given that circadian rhythm disruption is associated with impairments in cognitive performance similar to those found in age-related cognitive decline, the authors investigated whether exogenous melatonin administration would improve cognitive functioning in healthy elderly subjects. METHODS: This double-blind, placebo-controlled pilot study assigned 26 healthy elderly subjects to receive either melatonin 1 mg or placebo nightly for 4 weeks. Participants completed a sleep questionnaire and a battery of cognitive tests at baseline and at 4 weeks. RESULTS: Melatonin administration improved reported morning "restedness" and sleep latency after nocturnal awakening, and also improved scores on the California Verbal Learning Test-interference subtest. CONCLUSIONS: Melatonin administration at a dose of 1 mg nightly may be effective in improving certain aspects of cognitive functioning and subjective reports of sleep quality in elderly subjects. It may prove to be a useful therapeutic agent in the treatment of age-related cognitive decline.

15 Double blind study of melatonin effects on the sleep-wake rhythm, cognitive and non-cognitive functions in Alzheimer type dementia. J Nippon Med Sch 2003 Aug;70(4):334-41

Previously, we reported that morning bright light therapy improved sleep time and cognitive function in Alzheimer type of dementia. We conducted a double blind study to examine the effects of melatonin on the sleep-wake rhythm, cognitive and non-cognitive functions in Alzheimer type of dementia. The subjects were 9 persons given a placebo (PLA), and 11 given melatonin ( 3 mg)(MLT). The mean age was 79.2+/-6.4 (17 females and 3 males). The drugs were given at 20: 30 each day for 4 weeks. We checked sleep time and activity by Actigraph through one week before and the 4th week after drug administration. Cognitive and non-cognitive functions were evaluated with the clinical dementia rating scale (CDR), and Mini Mental State Examination (MMSE), and the Alzheimer's Disease Assessment Scale (ADAS). We successfully recorded Actigraph data from 18 patients (PLA8, MLT10). The mean sleep time change ratio and SD of the administration of PLA in the night was-0.2+/-13.7%, and MLT was 33.2+/-37.6%. The mean activity counts and SD of the administration of PLA in the night was 29.8+/-77.0%; in MLT it was-44.9+/-21.9%. Melatonin significantly prolonged the sleep time (p=0.017) and decreased activity (p=0.014) in the night (21: 00-6: 00) in the MLT group, although no significant difference in sleep time or activity in the daytime (6: 00-21: 00) was recognized between the two groups. In comparison with ADAS cognition score changes, the mean change and SD in the PLA was 0.3+/-3.7; in MLT it was-4.3+/-3.6 points. In comparison with ADAS non-cognition score, the mean change and SD in the PLA group was-0.8+/-1.0, in the MLT group it was-4.1+/-2.2 points. There were also significant differences between the PLA and the MLT groups in the comparison with the score improvement of ADAS cognition (p=0.017) and non-cognition (p=0.002), otherwise there was no significant difference in improvement of MMSE between both groups. Melatonin administration had effect to improve sleep time and night activity, but no significant effect to improve daytime naps and activity. Although melatonin administration might has less strong effect on circadian rhythm than morning bright light therapy we previously reported, cognitive and non-cognitive functions were improved. Melatonin seemed to be useful for care of the Alzheimer type of dementia patients.

16 Tazaki Y,Sakai F,Otomo E,Kutsuzawa T,Kameyama M,Omae T,Fujishima M,Sakuma A. "Treatment of acute cerebral infarction with a choline precursor in a multicenter double-blind placebo-controlled study." Stroke. 1988 Feb;19:211-6. (Issue number 2) Research reported by Department of Medicine, Kitasato University, Sagamihara, Japan.. =21504= = Author's abstract: A multicenter double-blind placebo-controlled study of cytidine 5'-diphosphocholine (CDP-choline) was conducted to evaluate possible clinical benefits of the drug in patients with acute, moderate to severe cerebral infarction. The patients included also suffered from moderate to mild disturbances of consciousness, and all were admitted within 14 days of the ictus. Patients were allocated randomly to treatment with either CDP-choline (1,000 mg/day i.v. once daily for 14 days) or with placebo (physiological saline). One hundred thirty-three patients received CDP-choline treatment, and 139 received placebo. The group treated with CDP-choline showed significant improvements in level of consciousness compared with the placebo-treated group, and CDP-choline was an entirely safe treatment.

17 Clark WM,Warach SJ,Pettigrew LC,Gammans RE,Sabounjian LA. "A randomized dose-response trial of citicoline in acute ischemic stroke patients. Citicoline Stroke Study Group." Neurology. 1997 Sep;49:671-8. (Issue number 3) Research reported by Oregon Stroke Center, Oregon Health Sciences University, Portland 97201, USA.. =21503= = Author's abstract: Citicoline (CDP-choline) is a key intermediary in the biosynthesis of phosphatidylcholine, an important component of the neural cell membrane. It has been shown to produce beneficial effects in both animal models and non-US clinical stroke trials. This study comprised a randomized (3 doses of citicoline to 1 placebo), vehicle-controlled, double-blind trial at 21 US centers. Treatment was to be started within 24 hours of stroke onset and was continued orally for 6 weeks. Final outcome assessments were at 12 weeks. Two hundred fifty-nine patients were enrolled, with approximately 65 in each of the four groups. Mean time from stroke onset to treatment was 14.5 hours, and there were no significant differences in baseline characteristics between the four groups except for patient weight. A significant difference between the groups, favoring citicoline treatment, was seen in terms of functional outcome as measured by the Barthel Index and Rankin scale, neurologic evaluation as measured by the National Institutes of Health (NIH) stroke scale, and cognitive function as measured by the Mini Mental Status Examination. When the baseline NIH stroke scale was used as a covariate, both the 500-mg citicoline group and the 2,000-mg citicoline group had a significant improvement in terms of the percent of patients who had a favorable outcome on the Barthel Index at 90 days. There were no drug-related serious adverse events or deaths in this study. This study suggests that oral citicoline can be used safely with minimal side effects in acute stroke treatment. Citicoline appears to improve functional outcome and reduce neurologic deficit with 500 mg of citicoline appearing to be the optimal dose.

Clark WM,Williams BJ,Selzer KA,Zweifler RM,Sabounjian LA,Gammans RE. "A randomized efficacy trial of citicoline in patients with acute ischemic stroke." Stroke. 1999 Dec;30:2592-7. (Issue number 12) Research reported by Oregon Stroke Center, Oregon Health Sciences University, Portland 97201, USA. Clarkw@ohsu.edu. =21502= = Conclusion: The results of this study indicate that citicoline was safe but ineffective in improving the outcome of patients with acute ischemic stroke who were enrolled in this trial. Post hoc analyses indicate that there may be a subgroup of patients with moderate to severe strokes who would benefit. = Author's abstract: BACKGROUND AND PURPOSE: Citicoline (cytidine-5'-diphosphocholine; CDP-choline) may reduce central nervous system ischemic injury by stabilizing cell membranes and reducing free radical generation. A previous dose-comparison trial in patients with acute stroke found that 500 mg of citicoline appeared to improve neurological outcome with minimal side effects. METHODS: The current trial was a 33-center, randomized, double-blind, efficacy trial in 394 patients comparing placebo (n=127) with citicoline (n=267) (500 mg po daily) for 6 weeks, with a 6-week posttreatment follow-up period. Patients with acute (24 hours) ischemic strokes clinically assessed to be in the middle cerebral artery territory with National Institutes of Health Stroke Scale (NIHSS) > or = 5 were enrolled. RESULTS: Mean time to treatment was 12 hours, and mean age was 71 for placebo and 70 for citicoline. Although mean baseline NIHSS were similar for both groups, there was a higher percentage of placebo patients with NIHSS <8 (34% vs 22%; P<0.01). The incidence and type of side effects were similar between the groups. The planned primary analysis (logistic regression: 5 categories Barthel) failed the proportional odds assumption and was rendered unreliable. There were no between-group differences seen on the planned secondary assessment analyses at 90 days, including the Barthel Index > or = 95 at 12 weeks (last observation carried forward: placebo 40%; citicoline 40%) or mortality rate (placebo 18%; citicoline 17%). However, post hoc analyses in a subgroup of patients with baseline NIHSS > or = 8 found that citicoline-treated patients were more likely to have a full recovery (Barthel > or = 95): placebo 21%; citicoline 33%; P=0.05; whereas no difference was seen in patients with baseline NIHSS<8 (placebo 77%; citicoline 69%; P>0.1.

Clark WM,Wechsler LR,Sabounjian LA,Schwiderski UE. "A phase III randomized efficacy trial of 2000 mg citicoline in acute ischemic stroke patients." Neurology. 2001 Nov 13;57:1595-602. (Issue number 9) Research reported by Oregon Stroke Center, Oregon Health Sciences University, Portland, OR 97201, USA. Clarkw@ohsu.edu. =21501= = Conclusion: Citicoline was safe but ineffective in improving the outcome of patients with acute ischemic stroke as measured by the planned analyses. Post hoc analyses suggest that a modest treatment effect may have been seen if more traditional analyses had been used. = Author's abstract: BACKGROUND: Citicoline may reduce CNS ischemic injury by stabilizing cell membranes and reducing free radical generation. Previous safety and efficacy trials in patients who have had acute strokes suggested that citicoline may improve neurologic outcome with minimal side effects. OBJECTIVE: To determine the safety and efficacy of citicoline treatment in acute stroke patients. METHOD: An 118-center, randomized, double-blind, efficacy trial in 899 patients compared placebo (n = 446) with citicoline (n = 453) (1000 mg PO twice a day) for 6 weeks, with a 6-week post-treatment follow-up period. Patients with acute (< or =24 hours) ischemic strokes clinically thought to be in the middle cerebral artery territory with NIH Stroke Scale (NIHSS) scores > or =8 were enrolled. RESULTS: Mean time to treatment was 13 hours for both groups and mean age was 67 years for those receiving placebo and 68 years for those receiving citicoline. Mean baseline NIHSS scores were 14.5 for placebo and 13.9 for citicoline (p = 0.06); medians were 14 for placebo and 13 for citicoline (p = 0.04). The incidence and type of side effects were similar between the groups. There were no between-group differences on the planned primary analysis, percent of patients with a > or =7-point NIHSS score change at 90 days (placebo 51%, citicoline 52%). There were no between-group differences on the other planned secondary analyses at 90 days, including mortality. However, post hoc analyses using standard "excellent recovery" measures suggested a possible treatment effect on the modified Rankin 0 or 1 (last observation carried forward: placebo 20%, citicoline 26%; p = 0.025) as well as a global outcome statistic.

18 Fioravanti M,Yanagi M. "Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly." Cochrane Database Syst Rev. 2005; page CD000269. (Issue number 2) Research reported by Department of Psychiatric Science and Psychological Medicine, University of Rome "La Sapienza", P.le A. Moro, 5, Rome, Italy, 00185. mario.fioravanti@uniroma1.it. =21493= = Conclusion: There was some evidence that CDP-choline has a positive effect on memory and behaviour in at least the short to medium term. The evidence of benefit from global impression was stronger, but is still limited by the duration of the studies. Further research with CDP-choline should focus on longer term studies in subjects who have been diagnosed with currently accepted standardised criteria, especially Vascular Mild Cognitive Impairment (VaMCI) or vascular dementia. = Author's abstract: BACKGROUND: CDP-choline (cytidine 5'-diphosphocholine) is a precursor essential for the synthesis of phosphatidylcholine, one of the cell membrane components that is degraded during cerebral ischaemia to free fatty acids and free radicals. Animal studies suggest that CDP-choline may protect cell membranes by accelerating resynthesis of phospholipids. CDP-choline may also attenuate the progression of ischaemic cell damage by suppressing the release of free fatty acids. CDP-choline is the endogenous compound normally produced by the organism. When the same substance is introduced as a drug it can be called citicoline.CDP-choline is mainly used in the treatment of disorders of a cerebrovascular nature. The many years of its presence in the clinical field have caused an evolution in dosage, method of administration, and selection criteria of patients to whom the treatments were given. Modalities of the clinical studies, including length of observation, severity of disturbance, and methodology of evaluation of the results were also heterogeneous. In spite of uncertainties about its efficacy due to these complexities, CDP-choline is a frequently prescribed drug for cognitive impairment in several European countries, especially when the clinical picture is predominantly one of cerebrovascular disease, hence the need for this review.Due to its effects on the adrenergic and dopaminergic activity of the CNS, CDP-choline has also been used as an adjuvant in the treatment of Parkinson's disease. OBJECTIVES: To assess the efficacy of CDP-choline (cytidinediphosphocholine) in the treatment of cognitive, emotional, and behavioural deficits associated with chronic cerebral disorders in the elderly. SEARCH STRATEGY: The trials were identified from a last updated search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 22 April 2004 using the terms CDP-choline, CDP, citicoline, cytidine diphosphate choline or diphosphocholine. The Register contains records from all major health-care databases and many ongoing trials databases and is updated regularly. SELECTION CRITERIA: All relevant unconfounded, double-blind, placebo-controlled, randomized trials of CDP-choline for cognitive impairment due to chronic cerebral disorders were considered for inclusion in the review. DATA COLLECTION AND ANALYSIS: Two reviewers independently reviewed the included studies, extracted the data, and pooled it when appropriate and possible. The pooled odd ratios (95% Confidence Interval (CI)) or the average differences (95% CI) were estimated. No intention-to-treat data were available from the studies included. MAIN RESULTS: Fourteen studies were included in this review. Some of the included studies did not present numerical data suitable for analysis. Description of participants varied over the years and by type of disorders and severity, and ranged from aged individuals with subjective memory disorders to patients with Vascular Cognitive Impairment (mild to moderate), Vascular Dementia or Senile Dementia (mild to moderate). Seven of the included studies observed the subjects for a period between 20 to 30 days, one study was of 6 weeks duration, four studies used periods extending over 2 and 3 months, one study observed continuous administration over 3 months and one study was prolonged, with 12 months of observation. The studies were heterogeneous in dose, modalities of administration, inclusion criteria for subjects, and outcome measures. Results were reported for the domains of attention, memory testing, behavioural rating scales, global clinical impression and tolerability. There was no evidence of a beneficial effect of CDP-choline on attention. There was evidence of benefit of CDP-choline on memory function and behaviour. The drug was well tolerated.

19 Acute and chronic effects of vinpocetine on cerebral hemodynamics and neuropsychological performance in multi-infarct patients.
Kemeny V, Molnar S, Andrejkovics M, Makai A, Csiba L.
J Clin Pharmacol. 2005 Sep;45(9):1048-54.
Department of Neurology, PM Flór Ferenc County Hospital, H-2143 Kistarcsa, and Department of Neurology, University of Debrecen, Hungary.

A double-blind, prospective, randomized, placebo-controlled clinical trial was carried out to test the acute and long-term hemodynamical and beneficial cognitive effects of the vasoactive agent vinpocetine on patients suffering from multiple cerebral infarcts by means of functional transcranial Doppler examinations and by neuropsychological tests. Twenty-six patients (17 men, 9 women) with multiple cerebral infarctions, aged between 50 and 83 years (mean age+/-SD=63.4+/-9.39 years) were examined, 14 of whom received vinpocetine and 12 placebo. The functional transcranial Doppler included breath-holding tests, finger movement, word fluency, and picture-discrimination tasks. Twenty-five patients were assessed by neuropsychological battery. No serious side effect was found in the vinpocetine group. The flow velocities were significantly lower in the acute phase after breath holding in the vinpocetine group than in the placebo group. Three months later, the vinpocetine patients did not show any significant worsening in digit span backward test, while the placebo group did. No other significant differences in the neuropsychological test could be detected between the treatment and the placebo groups. Longer lasting and higher dosage of vinpocetine therapy is suggested to prove its potential effect.

20 The chronic effects of an extract of Bacopa monniera (Brahmi) on cognitive function in healthy human subjects.

Neuropsychology Laboratory, School of Biophysical Science and Electrical Engineering, Victoria, Australia.

RATIONALE: Extracts of Bacopa monniera have been reported to exert cognitive enhancing effects in animals. However, the effects on human cognition are inconclusive. OBJECTIVE: The current study examined the chronic effects of an extract of B. monniera (Keenmind) on cognitive function in healthy human subjects. METHODS: The study was a double-blind placebo-controlled independent-group design in which subjects were randomly allocated to one of two treatment conditions, B. monniera (300 mg) or placebo. Neuropsychological testing was conducted pre-(baseline) and at 5 and 12 weeks post drug administration. RESULTS: B. monniera significantly improved speed of visual information processing measured by the IT task, learning rate and memory consolidation measured by the AVLT (P<0.05), and state anxiety (P<0.001) compared to placebo, with maximal effects evident after 12 weeks. CONCLUSIONS: These findings suggest that B. monniera may improve higher order cognitive processes that are critically dependent on the input of information from our environment such as learning and memory. Psychopharmacology (Berl) 2001 Aug;156(4):481-4

This is the most recent of several studies, not all of which have been positive.

21 Statins and cognitive function in the elderly: the Cardiovascular Health Study. Neurology 2005 Nov 8;65(9):1388-94

OBJECTIVE: To examine the association of statin drug use on cognitive and MRI change in older adults. METHODS: Participants in the Cardiovascular Health Study, a longitudinal study of people age 65 or older, were classified into three groups determined by whether they were taking statin drugs on a continuous basis, intermittently, or not at all. The untreated group was further divided into categories based on National Cholesterol Education Program recommendations for lipid-lowering treatment. Participants with prevalent or incident clinical TIA or stroke or with baseline Modified Mini-Mental State Examination (3MS) scores at or below 80 were excluded. Outcomes examined included rate of change on the 3MS over an average observational period of 7 years, along with changes in MRI white matter grade and measures of atrophy. RESULTS: Three thousand three hundred thirty-four participants had adequate data for analysis. At baseline, the untreated group in which lipid-lowering drug treatment was recommended were slightly older, less likely to be on estrogen replacement, and had higher serum cholesterol and lower 3MS scores than the statin-treated group. The rate of decline on the 3MS was 0.48 point/year less in those taking statins compared with the untreated group for which treatment was recommended (p = 0.069) and 0.49 point/year less in statin users compared with the group in which lipid-lowering treatment was not recommended (p = 0.009). This effect remained after controlling for serum cholesterol levels. One thousand seven hundred thirty participants with baseline 3MS scores of > 80 underwent cranial MRI scans on two occasions separated by 5 years. There was no significant difference in white matter grade change or atrophy measures between groups. CONCLUSION: Statin drug use was associated with a slight reduction in cognitive decline in an elderly population. This relationship could not be completely explained by the effect of statins on lowering of serum cholesterol.

22 Rozzini R,Ferrucci L,Losonczy K,Havlik RJ,Guralnik JM. "Protective effect of chronic NSAID use on cognitive decline in older persons." Journal of the American Geriatrics Society. 1996 Sep;44:1025-9. (Issue number 9) Research reported by Geriatric Evaluation and Rehabilitation Unit, P. Richiedei Hospital, Gussago (BS), Italy.. =11175= = Conclusion: These results support the association between NSAID use and reduction in cognitive decline in older persons. Ultimately, randomized controlled trials must be done to prove a beneficial effect definitively. = Author's abstract: OBJECTIVE: To verify whether chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) has a protective effect against cognitive decline in older persons. DESIGN: Prospective study with a 3-year observation period. SETTING: Three communities of the Established Populations for Epidemiologic Studies of the Elderly (EPESE). SUBJECTS: A population-based sample of 7671 subjects who received an in-person interview at the sixth annual follow-up. Persons with documented NSAID use at the time of the interview and 3 years before were considered chronic users (21%), while all other persons were considered as nonusers. MAIN OUTCOME MEASURE: Change over time in cognitive function assessed as the number of correct answers to a 9-item version of the Short Portable Mental Status Questionnaire (SPMSQ). RESULTS: For every level of SPMSQ score measured at the beginning of the observation period, the mean SPMSQ score after 3 years was higher in chronic NSAID users than in nonusers. Cognitive function at the end of the observation period was significantly higher in chronic NSAID users than in controls, adjusting for initial SPMSQ score and potential confounders. Older age, female gender, education, and history of cerebrovascular disease were also independent predictors of lower SPMSQ score. In the multivariate analysis, the magnitude of the protective effect estimated for NSAID use was comparable to a difference in age of 3.5 years. The percentage of persons who started above a specific SPMSQ score cut-point and deteriorated below that cut-point over a 3-year period was significantly lower in chronic NSAID users than in nonusers (30.2% vs 34.3%, P = .03, for decline below SPMSQ score of 8 and 12.3% vs 14.4% for decline below SPMSQ score of 6, P = .04). After controlling for potential confounders, the relative risk of cognitive declining in chronic NSAID users compared with nonusers was 0.82 (95% Confidence Interval: 0.69-0.98) for a decline below a score of 8, and 0.80 (95% CI: 0.66-0.98) for a decline below a score of 6.

23 Central auditory dysfunction, cognitive dysfunction, and dementia in older people. Arch Otolaryngol Head Neck Surg 1996 Feb;122(2):161-7

Department of Otolaryngology-Head and Neck Surgery, University of Washington School of Medicine, Seattle, USA.

OBJECTIVES: To determine in older people the relation between auditory dysfunction and cognitive dysfunction, and if central auditory test abnormalities predict the onset of clinical dementia or cognitive decline. DESIGN: Prospective population-based cohort study. SETTING: Framingham Heart Study outpatient biennial examinations 18 and 21. PARTICIPANTS: Members of the Framingham Heart Study cohort with normal findings from cognitive screening tests at biennial examination 18. MEASUREMENTS: Peripheral audiometric thresholds and word recognition in quiet; Synthetic Sentence Identification with Ipsilateral Competing Message (SSI-ICM); Mini-Mental State Examination; and detailed neuropsychological testing of subjects with abnormal findings from the Mini-Mental State Examination. Relative risk of dementia was determined using age-adjusted Cox proportional hazards regression models. RESULTS: Hearing loss significantly lowered performance on the verbal parts of the Mini-Mental State Examination. The relative risk of subsequent clinical dementia or cognitive decline was 6 in subjects with very poor scores (< 50%) in one ear on the SSI-ICM (P = .02); the relative risk was 12.5 if the poor scores were present in both ears (P = .001). CONCLUSIONS: Central auditory dysfunction precedes senile dementia in a significant number of cases and may be an early marker for senile dementia. Hearing tests should be included in the evaluation of persons older than 60 years and in those suspected of having cognitive dysfunction.

24 Neuroepidemiology 2006;26(3):140-6

25 Associations of vegetable and fruit consumption with age-related cognitive change.
Neurology. 2006 Oct 24;67(8):1370-6.

OBJECTIVE: To examine the association between rates of cognitive change and dietary consumption of fruits and vegetables among older persons. METHODS: The authors conducted a prospective cohort study of 3,718 participants, aged 65 years and older of the Chicago Health and Aging Project. Participants completed a food frequency questionnaire and were administered at least two of three cognitive assessments at baseline, 3-year, and 6-year follow-ups. Cognitive function was measured using the average z-score of four tests: the East Boston Tests of immediate memory and delayed recall, the Mini-Mental State Examination, and the Symbol Digit Modalities Test. RESULTS: The mean cognitive score at baseline for the analyzed cohort was 0.18 (range: -3.5 to 1.6), and the overall mean change in score per year was a decline of 0.04 standardized units. In mixed effects models adjusted for age, sex, race, and education, compared with the rate of cognitive decline among persons in the lowest quintile of vegetable intake (median of 0.9 servings/day), the rate for persons in the fourth quintile (median, 2.8 servings/day) was slower by 0.019 standardized units per year (p = 0.01), a 40% decrease, and by 0.018 standardized units per year (p = 0.02) for the fifth quintile (median, 4.1 servings/day), or a 38% decrease in rates. The association remained significant (p for linear trend = 0.02) with further control of cardiovascular-related conditions and risk factors. Fruit consumption was not associated with cognitive change. CONCLUSION: High vegetable but not fruit consumption may be associated with slower rate of cognitive decline with older age.

26 Alcohol intake in relation to brain magnetic resonance imaging findings in older persons without dementia. Tom den Heijer et al. Am J Clin Nutr 2004;80:992–7.

27 Cognitive activity and incident AD in a population-based sample of older persons. Neurology 2002 Dec 24;59(12):1910-4
Department of Neurological Sciences, Rush Alzheimer's Disease Center and Rush Institute for Healthy Aging, Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL 60612, USA.

BACKGROUND: Participation in cognitively stimulating activities is hypothesized to be associated with risk of AD, but knowledge about this association is limited. METHODS: A biracial community in Chicago was censused, persons aged 65 years and older were asked to participate in an interview, and 6,158 of 7,826 (79%) eligible persons did so. As part of the interview, persons rated current frequency of participation in seven cognitive activities (e.g., reading a newspaper) and nine physical activities (e.g., walking for exercise) from which composite measures of cognitive and physical activity frequency were derived. Four years later, 1,249 of those judged free of AD were sampled for a detailed clinical evaluation of incident disease and 842 (74% of those eligible) participated. RESULTS: The composite measure of cognitive activity ranged from 1.28 to 4.71 (mean 3.30; SD 0.59), with higher scores indicating more frequent activity. A total of 139 persons met National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for AD on clinical evaluation. In a logistic regression model adjusted for age, education, sex, race, and possession of the APOE epsilon4 allele, a one-point increase in cognitive activity score was associated with a 64% reduction in risk of incident AD (OR 0.36; 95% CI 0.20 to 0.65). By contrast, weekly hours of physical activity (mean 3.5; SD 5.1) was not related to disease risk (OR 1.04; 95% CI 0.98 to 1.10). Education was associated with risk of AD and a similar trend was present for occupation, but these effects were substantially reduced when cognitive activity was added to the model. CONCLUSION: Frequency of participation in cognitively stimulating activities appears to be associated with risk of AD and may partially explain the association of educational and occupational attainment with disease risk.

28 Lower cognitive function in the presence of obesity and hypertension: the Framingham heart study. Int J Obes Relat Metab Disord 2003 Feb;27(2):260-8

Department of Mathematics and Statistics, Statistics and Consulting Unit, Boston University, MA 02215, USA.

OBJECTIVE: To determine the independent effects of obesity and hypertension on cognitive functioning. METHODS: Using a prospective design, male (n=551) and female (n=872) participants of the Framingham Heart Study were classified by presence or absence of obesity and hypertension based on data collected over an 18-y surveillance period. All subjects were free from dementia, stroke, and clinically diagnosed cardiovascular disease up to the time of cognitive testing. Statistical models were adjusted for age, education, occupation, cigarette smoking, alcohol consumption, total cholesterol, and a diagnosis of type II diabetes. Body mass index status (nonobese or obese) and blood pressure status (normotensive or hypertensive) were then related to cognitive performance (learning, memory, executive functioning, and abstract reasoning) on tests administered 4-6 y later. RESULTS: Adverse effects of obesity and hypertension on cognitive performance were observed for men only. Obese and hypertensive men performed more poorly than men classified as either obese or hypertensive, and the best performance was observed in nonobese, normotensive men. CONCLUSIONS: The adverse effects of obesity and hypertension in men are independent and cumulative with respect to cognitive deficit.

29 Annals of Internal Medicine "Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older" 2006;144:73

30 Annals of Internal Medicine "Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older" 2006;144:73

31 The difference between couch potatoes who exercised three or more times per week and couch potatoes who exercised less was greater than the difference between fit people who exercised more and fit people who exercised least. "Fit" here means people who scored best on a fitness test.