© Whole Foods Magazine

September 2005


Phosphatidylserine and the Memory Cure

An Interview with Thomas H. Crook III, Ph.D.


By Richard A. Passwater, Ph.D.


The aging of the population and the recent approval of health claims for phosphatidylserine (PS) for the treatment of age-related mental decline give cause for us to revisit the encouraging research of the internationally recognized memory expert, Dr. Thomas Crook. As millions of people reach their mid-40s and beyond, many are experiencing the frightening, stressful and inconvenient problems of declining memories and mental decline. Dr. Crook has spent his career researching memory and memory loss and has summarized his findings that PS restores mental function in a very readable and understandable book with co-author Brenda Adderly, M.H.A.

The thesis of the book, which is entitled The Memory Cure (Pocket Books 1998), is that PS can slow, halt, or reverse the decline of memory and mental function due to aging. Dr. Crook, whose international research team has conducted comprehensive research in literally dozens of leading universities on virtually every drug developed since 1980 to treat Age Associated Memory Impairment (AAMI) states flatly, “PS is by far the best of all drugs and nutritional supplements we have ever tested for retarding AAMI.”

Dr. Crook is the author or editor of eight academic books, three books for the general public, more than 175 peer-reviewed scientific articles, and has delivered more than 300 invited academic presentations. After receiving his doctorate in psychology from the University of Maryland, Dr. Crook spent 14 years as a clinical research psychologist and research program director at the National Institute of Mental Health (NIMH) in Bethesda, MD. Dr. Crook is the former chairman of both the NIMH and American Psychological Association Task Forces on the diagnoses and treatment of age-associated memory impairment. He then expanded his clinical research by founding Memory Assessment Clinics, Inc. in 1985 and served as president for a decade as it grew throughout the United States and Europe and came to count among its clients most of the major international pharmaceutical companies. Dr. Crook currently serves as president and CEO of Psychologix, a company he founded in 1995 that conducts cognitive drug and nutraceutical trials worldwide.


Passwater: Dr. Crook, how did you become interested in psychology?


Crook: Well, I guess even as a kid I was struck by how very different people are from one another and how differently they respond to the same situation. In many respects, it seemed to me that these differences come about, in large part, because of the way people think about themselves and the world around them. I wanted to learn how each of us comes to learn, remember, think and behave as we do.


Passwater: Why memory? What attracted you to studying memory?


Crook: Memory seems to me to be at the very center of our individual identities. We all have good and bad memories, sometimes accurate and sometimes not, that are the basis for how we see ourselves and the world around us. Certainly, my fond memories from early childhood of my always-encouraging grandfather continue even today, half a century later, to be perfectly clear and still very important to my identity. I also saw how problematic memory can be from both psychological and neurological perspectives.

Psychologically, for example, one can focus on negative memories and discount, or even fail to encode, positive experiences and, predictably, the result is loss of confidence and dysphoria or depression.

Neurologically, of course, brain trauma and many diseases may cause profound and tragic memory problems. Over the years I have I seen so many cases that can only be described as heartbreaking, where a husband no longer recognizes his wife of 50 years, upon whom he is entirely dependent, or a woman whose entire adult life has been devoted to her children and grandchildren who has no memory of them and greats family members angrily as intruders intent on doing her harm.


Passwater: Dr. Crook, the overall message of The Memory Cure deals largely with overcoming Age Associated Memory Impairment (AAMI) with PS, plus a practical plan to maximize memory capabilities. Please tell us how bad the memory problem is. What have studies shown as to the degree of AAMI?


Crook: Age-Associated Memory Impairment (AAMI) is a diagnostic term adopted by a National Institute of Mental Health (NIMH) Workgroup that I chaired almost 20 years ago. The term describes people over 50 years of age who report that their memory has declined since early adult life, who show evidence on neuropsychological testing that such decline has occurred, and who have no medical or psychiatric conditions that could account for this loss. The diagnosis has been adopted since then by both the American Psychiatric Association and the American Psychological Association as a condition that is not a disease but a developmental condition that “merits attention and treatment.”

We then undertook an extensive series of studies examining the effects of aging on such important everyday memory tasks as remembering names of persons to whom one is introduced, remembering phone numbers, or remembering what one read in the morning paper. We studied tens of thousands of healthy, normal people around the world and found that the magnitude of loss on some of these important everyday tasks is really striking. For example, we found in a true random sample of the population of Italy, that the ability to remember names of persons to whom one is introduced declined by more than 65% between age 25 and 75. So, the prevalence of AAMI is quite high, rising steadily from about 40% at age 55 to almost 80% at age 85. In fact the prevalence is so high that we are clearly speaking of a “normal” developmental process. By the way, this phenomenon is not limited to humans, and occurs in monkeys, mice, marmosets and, indeed, in every mammalian species that has been studied.

Figures 1 and 2 summarize studies showing how people tend to lose their ability to remember names after being introduced to someone.


Passwater: What causes this impairment? Surely, it is not just the passage of time.


Crook: Well, those of us over 40 or so can see and experience changes that occur in skin, muscle and skeletal function, vision and other body systems as we grow older: surely, it is unreasonable to think that the brain would be insulated from the aging process. There are changes in neuronal function just as there are changes in muscle function and just as few middle-aged adults can run as fast as when they were teenagers, few can accomplish some memory tasks as quickly and as well.

Thankfully, this is not true of all memory tasks and not true at all of mental tasks that involve many types of intellectual function. It is of interest to me that several neurochemical systems related to memory and implicated in Alzheimer’s disease also diminish in the course of normal aging. Cholinesterase is an enzyme found primarily at nerve endings that catalyzes the breakdown of the neurotransmitter acetylcholine into acetic acid and choline. This reaction is necessary to allow a neuron to return to its resting state after activation. A cholinesterase inhibitor is a chemical that inhibits  cholinesterase enzymes from breaking down acetylcholine, thereby increasing both the level and duration of action of the neurotransmitter.) For example, four of the five prescription drugs currently on the American market are cholinesterase inhibitors that enhance cholinergic function (liberating acetylcholine) by blocking the enzyme responsible for the degradation of acetylcholine. But it is also true that there is diminished cholinergic function in the course of normal aging and evidence that these same drugs can modestly improve memory performance in healthy older humans and animals.


Passwater: What led you to investigate PS as a restorer of mental function?


Crook: We were systematically investigating compounds to treat AAMI based on neurochemical profiles, animal data, and any existing clinical data. Some of the compounds were quite specific new molecules. For example, we looked at two 5HT3 antagonists from major pharmaceutical companies and in both cases there was a compelling rationale and impressive pre-clinical data. Unfortunately, neither of these compounds was at all effective in the clinic.

Among cholinergic drugs, we were interested in M1 agonists and cholinesterase inhibitors. But all of these drugs had sufficient side-effects to disqualify them from serious consideration as AAMI drugs. In the search for cholinergic agents, we came across an Italian company, Fidia Pharmaceuticals, which was doing world-class work in developing drugs for neurological disorders. They already had PS on European markets and were seeking registration in the United States, so we agreed to conduct clinical trials to support that effort. There were very substantial safety data because PS was on the market and voluminous and impressive pre-clinical data. There was also very substantial clinical data but not in AAMI. We were interested but, as always, skeptical, particularly because PS had diverse neurochemical effects beyond the cholinergic effects.


Passwater: Just what does PS do biochemically?


Crook: PS stimulates the production and release of not only acetylcholine, but also norepinephrine, serotonin, and dopamine. It also speeds neuronal transmission by increasing the permeability of cell membranes. The real expert on the biochemical effects of PS is Dr. Parris Kidd, and he argues that brain cell membranes become rigid with age much as one can see with aging skin. Thus, PS has a fluidizing effect on these membranes, and that speeds signal transmission among neurons.


Passwater: What has been shown about PS supplementation in terms of function improvement?


Crook: There are many European studies showing that PS can improve learning, memory, concentration and attention in older people with evidence of memory impairment and also in patients in the very early stages of Alzheimer’s Disease (AD). It is most certainly not a cure for AD and is most effective in AAMI.


Passwater: What was your first study in your research with PS? What did you decide to look into first?


Crook: Our first study was conducted in my clinics, in Bethesda MD, and Scottsdale AZ, and at Stanford and Vanderbilt universities. We administered 300 mg of PS daily or a matched placebo to 149 subjects who met criteria for AAMI. Subjects were assigned to either the PS or a placebo group at random and both subjects and staff were blind to treatment assignment. Subjects were treated for 12 weeks and were tested at the end of weeks 3, 6, 9, and 12 with a sophisticated neuropsychological test battery measuring various aspects of learning, attention, and memory.


Passwater: What did you find?


Crook: Well, we found significant improvement on tests of memory and other cognitive abilities. That is, the PS and placebo groups differed at a statistically significant level after just three weeks of treatment on tests measuring such critical memory skills as recalling the names of persons to whom they are introduced, remembering telephone numbers, distinguishing between persons seen previously and those seen for the first time, and recalling where they had placed objects such as keys and eyeglasses. These differences remained highly significant after 12 weeks of treatment and disappeared three weeks after treatment was discontinued. The magnitude of improvement was impressive in that PS improved performance as much as 30% over placebo. We published this in the prestigious journal Neurology as the first AAMI treatment study they had accepted. Figure 3 summarizes some of our study results.


Passwater: I have seen those results, and they are astonishing! There are no drugs that can do that. PS is a safe nutrient and it can restore a decade of mental decline. Your study found that PS could restore the ability to remember names by 14 years and learning and remembering written information by nearly a dozen years. That is important and significant. Old dogs can learn new tricks and so can old people.

Where did this study lead you? What did you want to look at next?


Crook: We were ready to go on and examine different dosage levels and treatment regimens and to pursue full-scale development of PS as a prescription drug for AAMI. I should say that our study was done under an Investigative New Drug approved by the FDA. However, we immediately came across a problem that halted all of our PS research and other PS research worldwide, as well as requiring the withdrawal of PS from European markets. The compound we studied was labeled as BC-PS and the BC stood for bovine cortex.

PS is not only highly concentrated in human brain but also in the brains of animals. BC-PS was derived from the brains of cattle slaughtered for meat. This was 1991 and, of course our problem was that a possible link was emerging in England between consumption of cattle, particularly brains and internal organs, infected with Bovine Spongiform Encephalopathy and development of a variant of Creutzfeldt-Jacob disease in humans. Our BC-PS did not come from British herds and was not infected, but, in the interest of safety, all PS research was halted. Not until 1995 was a form of PS introduced that was derived from soy and was, thus, safe to test further.


Passwater: And what did you do then?


Crook: The Dietary Supplement Health and Education Act (DSHEA) had been passed in October of 1994, and interest shifted to developing PS as a dietary supplement to improve memory among persons with memory loss in middle and later life (i.e., AAMI). As we all know, the huge resources available for research in the pharmaceutical industry are simply not available for testing dietary supplements. Nevertheless, with the help of Peter Rohde, now at Science and Ingredients, we were able to conduct a study of 55 AAMI subjects using the same methodology as in the earlier study and we found the same, in fact slightly better, cognitive-enhancing effects.


Passwater: Based on your research, what can we conclude? What have you elucidated for us?


Crook: PS is on the market as a dietary supplement, and we have shown it safe and effective in AAMI. I am confident that the research we and many others are engaged in will bring other effective drugs and nutraceuticals to market for AAMI and the many other conditions that can impair memory. I think, though, that we must keep these drugs and dietary supplements in perspective. When we treat heart disease, for example, we do not simply prescribe anti-hypertensives and cholesterol-lowering drugs without encouraging patients to change their lives by exercising, improving their diet, losing weight and so on. In a similar manner, these same factors, together with mental exercise, will act with effective drugs or dietary supplements to improve memory in mid and later life.


Passwater: It appears to me that there seems to be a slowing down of research with PS and mental function. Is that my imagination or what?


Crook: No, I think you are correct. Since PS is not protected by patent, there is little incentive for companies to fund further research when existing data can support claims related to memory. If a pharmaceutical company had proprietary rights to PS we could do some very interesting studies, but that is not the case. At least it is good to see that existing evidence about the effects of PS in AAMI continues to filter down to people who can benefit. PS sales have increased steadily in recent years as a number of other putative memory-enhancing compounds have dropped precipitously.        


Passwater: Do you plan to conduct more studies with PS?


Crook: I would certainly like to do more with PS alone, but also in combination with omega-3 fatty acids, particularly DHA. I am also very enthusiastic about a little-known phospholipid derivative, GlyceroPhosphoCholine (GPC) which has been shown in a number of clinical trials to improve memory, attention, concentration, speed of recall and also mood. I am very keen to look at GPC in AAMI.


Passwater: What do you see in the near future? Is there exciting news about PS on the horizon? Will people be able to go to clinics and have their mental function evaluated and then be put on programs to restore them to normal?


Crook: Gosh, I was almost alone in thinking about this kind of business model 20 years ago when I founded Memory Assessment Clinics. I remain confident, though, that viable businesses can be built around mental fitness just as they are around physical fitness, and many others now share that belief. Aging baby boomers are not just going to sit back and meekly accept the loss of mental or physical capabilities as they grow older. They must be realistic, however: just as diligent, lifelong joggers in their 60s and 70s are still not likely to outpace their grandchildren in a 100-yard dash, neither are most of us at that age going to learn a new language or master a new piece of software as quickly as a 16-year-old. Mental function is different, though, in that I cannot think of a physical capacity that improves in later life while clearly we grow wiser with age and, with that wisdom, our goal should be to remember that which is adaptive to remember and forget that which is best forgotten.


Passwater: Thank you Dr. Crook, for your research that has restored mental function to so many people and thanks, too, for taking the time to chat with us about PS and your research. Your book, The Memory Cure, has much more to offer than discussions about PS. Our readers should also be interested in your six-step plan for sharpening mental skills and your discussion of how memory works. There is a lot of interesting information there that may surprise many readers. WF


© 2005 Whole Foods Magazine and Richard A. Passwater, Ph.D.

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