A Possible Treatment for the Learning Disability Associated with Down Syndrome

Don Stoner and son Josh

Summary:

1) Research with mice suggests that the learning disability associated with Down Syndrome might be treatable. (The results suggest complete restoration.)

2) The treatment consists of a common dietary supplement (EGCG), which is naturally occurring, inexpensive, and readily available over-the-counter. (You can probably get some from a local vitamin or drug store today.)

3) EGCG has been extensively tested with humans. The only known safety issues are considered to be extremely minor: mild iron loss (seldom a problem) and rare allergic reactions. (It's, quite literally, every bit as safe as drinking green tea is.)

4) EGCG appears to have helped our 12-year-old, Down-Syndrome son with his memory related problems. (And you don't have to take our word for it; you can try it yourself. We could see the difference within a few days.)

If you decide to try the experiment, then you will want to study all of the information given below before you do. Be sure to read all of the labels and consult your "health practitioner" or "physician" where requested. This web page is not intended to diagnose, treat, cure, or prevent any disease; it is provided only as information to those who might be considering doing their own research.


Contents:

Some History
The Experiment
Human Testing?
Side Effects
. Allergies (Update)
. Iron Loss (Update)
. Fluoride (Update)
. Birth Defects (Update)
. Liver Toxicity (Update)
Test it Ourselves?
Quantities to Try
EGG Sources
--- Updates ---
Alzheimer's
Alternate Treatments?
Prenatal/Nursing Treatment?
Anti-coagulant Properties


Full text, revision: 2011/10/23, By Donald W. Stoner

Don Stoner and son Josh

I had no interest at all in Down Syndrome research until November 15th of 1997, when I became the father of a Down Syndrome child named Joshua; then everything changed. Since then, I have been studying and closely watching the news for any chance of a treatment which might reverse Joshua's learning disability (which, in his case, seemed to be the worst part of his condition). Shortly after Josh was born, I discovered the research at U. C. Berkeley on transgenic mice; (in that case, the mice had been genetically altered to have what appeared to be the same Down Syndrome learning disability that Josh had). The researchers had isolated the part of the DNA, and the particular part of the cellular chemistry, which was probably responsible for my son's condition; (it's called DYRK1A).

Later, I followed the development while some some very expensive and potentially dangerous antiDYRK1A drugs began showing promise of reversing my son's condition. Even though I understood the risk, after watching Josh struggle to learn things that his siblings learned effortlessly, I found myself wondering whether it would be better if he were part of these early experiments, rather than just sitting by and waiting, while he continued to fall farther and farther behind other children who were born at the same time.

effect of green tea on transgenic mice, Down Syndrome Finally I came across a research article1 that reported what had been done with a very inexpensive, and apparently quite safe, substance called Epigallocatechin gallate (EGCG). EGCG appeared to bring about a full reversal of the learning disability in the transgenic mice which the researchers had used. Here (right) is a graph from figure 4 of that article. If I understand this graph correctly, it shows the effectiveness of EGCG as a possible treatment. The dark bars are the transgenic (TG) or Down's mice, and the lighter bars are the wild type (WT) or normal mice. The left two bars are the water-fed (H2O) mice, and the right two bars are the mice which have been fed a preparation (GTP) containing EGCG instead. The vertical axis (N-F)/(N+F) is intended to be a representation of learning ability ("N-F" is the difference between new and familiar situations; this is normalized by (N+F) which is all situations).2 What this graph illustrates, is that the Down's mice have a learning ability which, as we might have expected, is indistinguishable from zero (within the accuracy of the experiment) when they are fed water; but that they achieve a learning ability which is indistinguishable from normal mice when they are fed GTP (containing EGCG) instead.

DYRK1A is over expressed in Down Syndrome individuals (they have 50% too much of it). This causes them to have difficulty transferring information from their short-term memory to long-term memory. It appears that, somehow, EGCG removes this difficulty without causing any other difficulties. If anything, the graph suggests that EGCG might even be of some help to normal individuals as well. It seems to do everything good that it should do, and nothing bad.

green tea possible treatment for Down Syndrome memory disorder So, when might we expect human testing of EGCG, as a treatment for Down-Syndrome-related learning disability, to begin? Ironically, the low cost and relative safety of EGCG may be working against this happening any time soon. In order to justify the large amounts of money which might be required for a properly controlled scientific test, there would have to be a reasonable chance that the investment could be recovered by selling the final product. In this case there isn't; this is because EGCG is simply a major component of plain old green tea. The GTP/TG mice in the experiment simply drank green tea instead of water; since it was a scientific experiment, the recipe for brewing the tea was even provided (although in somewhat technical terms):

"Treatment was prepared daily. In the first set of experiments, mice were fed green tea ad libitum (1 g in 100 ml water for 5 min at 100 deg C), corresponding to 0.6-1 mg EGCG per day."

In layman's terms, the scientists brewed 70%-stronger-than-normal-strength green tea, in boiling water, for five minutes; and the mice drank as much as they wanted. In order to sell this treatment at a profit, the medical community would have to compete, quite literally, with "all of the tea in China." (In spite of the low potential for financial gain this research foundation in spain expects to have results of human testing within a few years.)

EGCG possible treatment for Down Syndrome
memory disorder EGCG possible treatment for Down Syndrome
memory disorder Further, EGCG is already commonly extracted from tea and sold as an inexpensive, well-distributed, (and decaffeinated) dietary supplement. It is already readily available, on the shelves of vitamin stores, in many forms and dosages. It is also labeled, "This product is not intended to diagnose, treat, cure, or prevent any disease," so there is no additional cost related to medical overhead. At least for the moment, this means that those of us who are parents of Down Syndrome children are kind of left to figure out what to do on our own.

The experiments with mice and EGCG seem to suggest that if our Down's children drink nothing but green tea, their learning disability might stop being a problem. (More benefits were obtained when mice were treated early, but even the mice who were not treated until adulthood showed the long-term memory improvement.)

What might be the danger in drinking green tea exclusively? Any change in diet is likely to carry some unintended consequences; even something as benign as green tea should be treated with some caution. According to this source: One negative consequence of green tea is that it tends to interfere with the body's ability to absorb iron. However, as the same source explains:

"There are two kinds of dietary iron: heme and non-heme. Heme iron, found in meat, fish and poultry, is absorbed by the body very efficiently. Non-heme iron, found in flours, cereals, and fortified grain products, is more difficult to absorb."

A person who gets iron from meat shouldn't have this problem; and in any case, as Wiki Answers appears to suggest, people with Down Syndrome often (not always) have iron levels which are too high. But this may still be something to watch. A vegetarian, for example, might have to be careful about iron levels with large amounts of green tea, as might a woman during her monthly cycle.

Epigallocatechin gallate Another concern would be any other significant toxic effects of large amounts of EGCG (chemical diagram at right). Studies have found none even for people who drink large amounts of green tea. (But see the "updates" below for our personal experience with allergic rashes.) According to the Herbs-Tech web page on EGCG:

"Green tea consumption of as much as 20 cups per day has not been associated with any significant side effects. Acute studies reported the oral LD50 [(Lethal Dose for 50% of subjects)] of EGCG in mice was 2170mg/kg bw."

Even assuming a relatively small 15g mouse, this would be: .015kg x 2170mg/kg, or about 32mg. This is 32 times as much as the mice in the study were given! The effective dose is not even close to the lethal dose.

There is no reason to expect exactly the same results with humans as have been obtained with mice; but since the treatment consists of nothing more dangerous than green tea (or some kind of EGCG green-tea dietary supplement), no great harm might be expected either. Balancing the down side of the long-term-memory learning disability of Down Syndrome against the unlikely, and relatively mild, potential side effects of an EGCG experiment, the choice of whether or not to modify diet should not be too difficult.

An EGCG dietary supplement might be significantly more convenient than keeping green tea constantly available (some brands are also less expensive than green tea). One supplier claims that their 200-milligrams-of-EGCG capsule contains the equivalent of about 2-3 cups of green tea. This suggests that one cup of green tea might contain about 80 milligrams of EGCG. (Even 6 of these capsules or 1200mg would be less than a safe 20 cups/day). Tracking how much fluid a child drinks, and multiplying the number of cups by 80 milligrams, might be a reasonable way to approximate what quantity to try in an experiment.

Mouse size variation Down Syndrome research Another way might be to start with the .6-1 milligram fed to the TG mice daily and scale it up for the weight of the selected test subject. Unfortunately, the experiment does not appear to specify the average weight of the mice used. According to WikiAnswers, the average laboratory mouse weighs, "About 20 grams but the weight varies from mouse to mouse."

We might choose to start toward the high side, not particularly fearing the consequences of overdosing on green tea, and wanting to be confident that we were using a sufficient quantity of EGCG to see some result. In this case we might assume the experimenters used the high end of the .6-1 milligram range on smaller than average mice (maybe 15 grams). The simple way to do dosage scaling is by raising the dosage by the 2/3 power of the weight ratio, which is scaling by surface area as explained here. However, the metabolic rate appears to scale at a slightly higher rate (the 3/4 power instead of the 2/3) as explained here. To put our starting estimate on the high side, we would scale a 1 milligram dose for a 15 gram mouse up by the 3/4 power to the weight of the mammal that we might intend to use in our experiment (an animal anatomically similar to the mouse). This rough scaling method produces the following (when converted to familiar English units):

---------- ---------- ----------
Weight of Quantity Approximate Green
"Mammal" of EGCG Tea Equivalent
poundsmilligrams/daycups/day
---------- ---------- ----------
10 73 - - - (7 1/3 oz)
11 78 1 -- (7 3/4 oz)
12 83 - - - (8 1/3 oz)
13 88 - - - (8 3/4 oz)
14 93 - - - (9 1/3 oz)
15 98 - - - (9 3/4 oz)
16 103 - - - (10 1/3 oz)
17 107 - - - (10 2/3 oz)
18 112 - - - (11 oz)
19 117 - - - (11 2/3 oz)
20 1221.5 (12 1/5 oz)
25 144 - - - (14 oz)
30 166 2 -- (16 0z)
35 185 - - - (18 oz)
40 2052.5
50 243 3
60 2783.5
70 3133.9
80 3454.3
90 3774.7
100 4085.1
110 4395.5
120 4685.9
130 4976.2
140 5266.6
150 5546.9
160 5817.3
170 6087.6
180 6357.9
190 6618.3
200 6878.6
---------- ---------- ----------

If we have done everything correctly, we might expect the cups/day column to reflect the approximate volume of liquid that we might expect the corresponding mammal to consume. I'm guessing that most people drink more fluids than my right-hand column predicts. (And using tea which was 70% stronger would only make the dosage, in cups, that much less than the normal amount of fluids consumed.) This suggests that my numbers may be slightly low, in spite of being chosen to be on the high side. Of course the methods I have used here are all very rough guesses, so some future refinement is expected.

Another possible problem is that the mice tended to drink their tea at a relatively steady rate over the course of the day; if EGCG tablets are used instead, the dosage will come in bursts. I don't know how much of a problem this might become; maybe the dose should be broken into halves which could be given twice a day; maybe even smaller fractions more often would be better.

(Originally, I tried making the minimum assumptions, but didn't see any significant change; then I switched to the maximum assumptions (half in the morning and half in the evening), with what appears to have been a quite significant improvement in long-term memory. My son, for the first time in his life, now remembers where he has put things.)

Does this sound interesting to you? If it sounds very interesting, then be sure to read all of the labels and consult your "health practitioner" or "physician" where requested. This web page is not intended to diagnose, treat, cure, or prevent any disease; it is provided only as information to those who might be considering doing their own research. Hopefully we still have the freedom to select our own over-the-counter dietary supplements and to discuss what we perceive to be the results.

Here are several different internet sources for EGCG:
Vitamin Menu,Source Natural, 30-33mg EGCG, 30 tablets
Vitamin Menu, Source Natural, 30-33mg EGCG, 60 tablets
All Vitamins Plus, Source Naturals, 35mg EGCG, 120 tablets;
Amazon, Good N Natural, 175mg EGCG, 120 capsules;
Amazon, Now Foods, 200mg EGCG, 90 vcaps;
Swanson, Now Foods, 200mg EGCG, 90 vcaps;
Less pure (less than 200mg EGCG), Now foods, Green Tea Extract, 250 vcaps;
Swanson, Now Foods, 200mg EGCG, 180 vcaps;
Vitacost, 240mg EGCG, 90 capsules;
Amazon, ProHealth, 290mg EGCG, 100 capsules;


Updates:

We started using "vcaps" (200 mg. EGCG each) on 2010/04/09. (Josh weighs 110 lbs., so we are giving him one in the morning and one in the evening for 400 mg/day.) The changes seemed to have started happening by the next day. (For example, Josh remembered where he had put his glasses for the first time in his life.) It has now been two weeks, and everything still looks good. I'll make a more complete report when I know more. -Don

We upped the dose from two to three "vcaps" (200 mg. EGCG each) on 2010/05/02. It wasn't obvious to us if there was an additional slight improvement or if things were going about the same (still good). However, on 2010/05/13, Josh had a mild rash; we have stopped the EGCG and are watching the rash to determine if it is related (he has been sick, so there are other complications here). Although adverse reactions to green tea are rare, they do exist. For example, here is a site which says the following about possible side effects:

"All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Green Tea:
"Constipation; diarrhea; nausea; restlessness; stomach upset; tremors; trouble sleeping.
"Seek medical attention right away if any of these SEVERE side effects occur when using Green Tea:
"Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); fast or irregular heartbeat; mental or mood changes."

According to this site here:

"The relationship between green tea and skin rash is complex. Tea tannin and caffeine can cause allergy. But green tea may cure it.
"While green tea contains caffeine and tannins that may cause skin rash, it also contains antioxidants that have been shown to combat allergy and inflammation."

Unfortunately, EGCG is the main constituent of tannin. It would be truly unfortunate if Josh turns out to be allergic to the only treatment presently available for his condition. (The "vcaps" we are giving Josh contain very little (4 mg per "vcap") caffeine, which would have been a concern to us even if it had no allergic consequences.) Here is some more about green tea allergies.

Update 2010/06/09: It seems Josh may have a mild allergic reaction to EGCG in excess of 400 mg/day. We have backed off to 400 mg/day (and are sometimes mixing smaller fractions, at a time, it in yogurt or drinks). Josh has not had any more allergic symptoms. He continues to show gradual memory improvement (knows more things), including using longer sentences (spontaneously) and understanding increasingly more complex requests. We are watching closely for any allergy symptoms; and have been researching possible antihistamines to try out if they should become necessary. Cetirizine HCL (Aller-Tec, available from Costco), among others, has been suggested.

Costco, Aller-Tec
DAB Nutrition, Aller-Tec
Meniamit, Aller-Tec
Amazon, Generic Benadryl (probably too extreme)

(At present, we are trying to avoid antihistamines because they might be just one more thing which Josh could have some kind of bad reaction to.)
Always read everything on the labels and consult with the necessary professionals.

Update 2010/07/06: There seems to be some connection between Down Syndrome and Alzheimer's. In particular, (as that link explains), "Nearly all individuals with Down syndrome progress to Alzheimer's dementia by the fifth or sixth decade of life." Interestingly, although other treatments are being explored, it appears that EGCG might turn out to help with this other problem as well. Naturally, my wife and I are both testing this theory as well (on ourselves). Although we are in no position to be at all objective about the results, so far it looks pretty good; now we are starting to remember where we have put our own glasses!

Update 2010/09/14: It seems like things are continuing on like normal (which is good). We are still seeing the same gradual improvement we might expect from a 12-year-old who only started learning at a normal rate a few months ago. The "miracle" jump from "no" memory to "normal" memory is months in the past; and now we we must practice patience as the next few years of "normal" development can do their work of "undoing" the past. Once we missed Josh's EGCG for about a day and were promptly punished when Josh was once again unable to remember where he had left his glasses; apparently the effects of the EGCG stop as quickly as they begin. A day later, with the EGCG, and we were back to normal; so the "miracle" is still at work, even if we are now, more or less, taking it for granted.

It seems like more of our friends' D.S. children have experienced mild rashes than the literature suggests should be normal. Maybe this is because we only hear about the problems, or maybe D.S. children are more susceptible; I don't really know. Like with introducing any new food, proper caution is important. This may be particularly important, in this case, since there seems to be much to be gained, over the long term, if we can avoid having a little bit of short-term impatience possibly "set off" a long-term allergy to EGCG.

It is becoming increasingly clear to my family that my own memory is better with EGCG. I'm about 170 lbs. and taking 1000mg of EGCG daily (equivalent to about 12.5 cups of tea). I'm purposely going on the high side (although the article quoted above actually suggests 1500-1600mg) so I'll be more likely to understand any difficulties my son might encounter as a result of exposure to EGCG. The only possible side effect I've noticed is that I think my skin seems to have become slightly more sensitive to "itchy" fabrics than normal. (That has always been a problem for me anyway; I always wear cotton instead of wool or polyester).

Update 2010/09/20: This past week I tried increasing the amount of EGCG I was taking from 1000mg daily to about 1400mg (about twice what my table above suggests I should take). I wasn't aware of any obvious additional improvement in my memory, but I did start noticing a "lightness" or "dizziness" in my head which I recognize as resulting from iron deficiency. I immediately backed off to 1000mg and started taking iron supplements; the "dizziness" stopped within a day. I wouldn't recommend going much over what the above table suggests in any experiment you might try -- and keep a close eye on iron levels.

This last week I also ran across a web site called Changing Minds Foundation that is discussing some other possible treatments for Down Syndrome (also based on experiments with mice, since no human tests have been completed yet). They are suggestion a combination of treatments for different parts of the Down Syndrome disorder. I found these alternatives to be worth studying, but I will be sticking with just EGCG, at least for the present. Here are some of the reasons for my choices regarding the suggestions which that site has made:

Ginkgo Biloba (for the short-term to long-term memory issues): See here for a technical site which appears to suggest that this (or something like it) might be helpful; but see here for a more skeptical position regarding its effectiveness. Ginkgo Biloba looks pretty safe; but it still has some possible problems, (see here for side effects). In particular, it has one of the same major downsides that EGCG has; Ginkgo Biloba chelates and removes iron from your system so you still have to watch your iron levels if you use it instead of EGCG. As long as Josh's mild EGCG allergy "keeps its head down" I think I won't take the chance of experimenting with any new potential problems.

Prozac (for the brain-development issues): See here for a slightly more skeptical position. This one has some fairly serious side effects, in addition to requiring a prescription. Since this research here makes the same claims for EGCG; I decided not to expose Josh to additional risk.

Phosphatidylcholine (for Alzheimer's related issues): See here for possible side effects. This one looks relatively safe. But, again, this research here makes the same claims for EGCG.

Focalin XR (for ADD/ADHD related issues): See here for more skeptical position. See here for possible side effects. This one scares me a little. Unfortunately, EGCG offers no help with this area. In any case, Josh hasn't had too much trouble here so we, personally, don't have to deal with it.

Since it appears I can get the claimed benefits of three different treatments with the side effects of just one (and a mild one at that), I'm planning on continuing my experiment using EGCG alone, as long as Josh's EGCG allergy doesn't become a problem. But the CMF site is still very interesting for many reasons; in particular, it is probably a very good place to swap ideas and results with other parents of Down Syndrome children.

Here is another (earlier, 2008) research paper which used EGCG as a DYRK1A inhibitor.

Update 2010/09/22: An issue regarding the safety of the fluoride content of green tea has been raised. This site explores the issue in some detail -- recommending a maximum of six cups per day. This recommendation probably applies to an "average" person, although that site uses very general terms and doesn't bother specifying. According to Wikianswers, an average person might weigh about 155 lbs. The table I calculated (above) suggests about seven cups for a person weighing 155lbs. I, personally, doubt that this would cause any kind of trouble, but anyone who has a concern with fluoride levels could easily scale back to 6/7 of the amounts I've suggested, when they do their own experiments.

Update 2010/09/24: According to this article, EGCG is able to cross the placental barrier, potentially allowing treatment to begin before birth -- by simply giving the mother EGCG. This was mentioned briefly in the original research article; but I had forgotten to mention it earlier. (I presume the same would be true for nursing mothers; give the mother the EGCG, and the child will get it through the milk.) My first guess would be that the amount to give the mother would be based on her weight (or her weight plus the child's); but I presently have no way to confirm this. However, medicating pregnant and nursing mothers can be tricky (particularly early in the pregnancy). More about this will be explained in the later updates.

Update 2010/10/04: According to this source here, "Pregnant or breast-feeding women should not drink green tea in large amounts." Considering the various potential side effects of EGCG, this may be very good advice. Always get the necessary professional help.

Speaking of side effects, like Aspirin and Ginkgo Biloba, EGCG appears to act as an anti-coagulant (commonly called a "blood thinner"). According to this source, "The potency of EGCG is comparable to that of aspirin," in this regard. However, the overall effect can be somewhat complicated; as this source explains, "Green tea contains small amounts of vitamin K, which can make anticoagulant drugs, such as warfarin, less effective." Drug combinations can have very complicated consequences.

Always read everything on the labels and consult with the necessary professionals.

Update 2011/01/24: I have received a few e-mails from some D.S. parents citing sources which had concerned them that EGCG might inhibit our children's growth. Since my son had gone through a good growth spurt immediately after we started giving it to him, I wasn't particularly worried; but the research which they cited did bring up some important information: Quoting from this study's concluding remarks:

"We have shown for the first time that gallated tea polyphenols act as DHFR inhibitors in vitro and in vivo, at concentrations usually found in the blood of tea drinkers. The “soft” character of such compounds could be developed for use in the prevention and treatment of cancer with significantly reduced side effects compared with those of the DHFR inhibitors currently in use in chemotherapy, such as methotrexate. An advantage of EGCG is its differential effects on normal and cancer cells. Importantly, at physiologically attainable concentrations, EGCG kills cancer cells through apoptosis, but has little or no effect on normal cells."
This study demonstrated that EGCG looked like a good way to inhibit the growth of cancer cells without causing significant harm to normal cells. This is normally a good thing; but there seems to be some kind of connection between cancer growth and foetal development (see here for more detail on that connection).

In particular, there is a statistical link between large amounts of EGCG and some catastrophic birth defects (anencephaly and spina bifida -- both developmental failures). This was mentioned at the very end of the article which I quoted above (linked by footnote #20 to this study here). To be safe, the increased risk might be offset by folic acid supplements, as explained by this source here; or, safer yet, a pregnant mother could simply avoid large amounts of EGCG during the time near conception, and, to a lesser degree, also during the first twelve weeks of her pregnancy. (Note: It might also be worth checking to see if folic acid increases the risk of cancer, since it seems to be pulling in the opposite direction that EGCG does, in this particular regard.)

Also: I received a letter today alerting me to something else which we need to watch out for. According to this report here:

Case reports on the toxic effects of green tea extracts in humans are also beginning to emerge. "To date, there have been nine anecdotal case reports of liver toxicity in humans associated with consumption of high doses [700–2,000 mg/day] of green tea from dietary supplements," says lead author Joshua Lambert, an assistant research professor in the Department of Chemical Biology at Rutgers University.

Some individuals appear to be more susceptible to liver toxicity than others; and the dosages where this begins to become a problem are not very much higher that what my table (above) suggests for a 200 lb. individual. (In fact, the dose I have been giving myself is within this range.) Some individuals might be much more sensitive than others; please take proper caution!

I repeat: Always read everything on the labels and consult with the necessary professionals.

Update 2011/10/22: It's been about a year and a half since we started Josh on EGCG. Today he attended a birthday party for his friend Joey at a rock-climbing gym:
-- --
He had a blast climbing that wall three times and actually worked up a sweat. I asked Debbie (my wife, "belaying" Josh in the pictures) if she had any ideas about why he had done so well; she reminded me that he had done this before at summer camp. An hour or so later, I realized that we were both taking it for granted that once Josh learns a skill, he still has it months later.

The spontaneous talking is progressing slowly; Josh did say, "Happy Birthday Joey!" to his friend -- without prompting.

Who Made God?
A very special Thank You to: Faycal Guedj, Catherine Sebrie, Isabelle Rivals, Aurelie Ledru, Evelyne Paly, Jean C. Bizot, Desmond Smith, Edward Rubin, Brigitte Gillet, Mariona Arbones, Jean M. Delabar, and to any others who have contributed to this research!
Footnotes:

1."Green Tea Polyphenols Rescue of Brain Defects Induced by Overexpression of DYRK1A", by Faycal Guedj, Catherine Sebrie, Isabelle Rivals, Aurelie Ledru, Evelyne Paly, Jean C. Bizot, Desmond Smith, Edward Rubin, Brigitte Gillet, Mariona Arbones, and Jean M. Delabar, Published February 26, 2009.

2. I originally thought (incorrectly) that the N and F were reversed; I have now figured out my mistake (possibly because the EGCG I'm taking has cleared up my thinking); and I apologize to the authors for accusing them of a mistake which was completely my own. I also can't thank them enough for helping both my son and me with our different memory problems.