can sleep be as easy as GB?

NO.   No. no. it can't be as easy  as Ginkgo biloba around the clock. Can a gaba antagonist be that  important? I gave Neal GB 120 mg before bed 4 nights in a row. Could that be the answer to the sleeping problem? The next morning  he told me ' I slept well and I am in SUCH a good mood!" Can that even be possible? I am not adding words to his sentence or filling in any blanks. That is what he said yesterday morning. 
Does it mean we give a GABA antagonist around the clock? I don't know. But it does make sense.  Wouldn't it be important to be balanced  all day and all night?
This morning he told my husband, "I'm not tired."
Don't jump to any conclusions from only 2 days but I got the idea from a study.
GABA A Receptors Inhibit Acetylcholine Release in Cat Pontine Reticular Formation: Implications for REM Sleep Regulation 
The entire study is available online. They used a GABA antagonist and triggered REM sleep. Neal has 2-3% REM in sleep studies [he has had 2]. I'm about to set up a third study. I'll let you know how it turns out.
I don't know why but I never thought about Ginkgo Biloba's half life before. Ginkgo's 1//2 life is about 6 hours and the Biloba piece has about a 3 hour 1/2 life. Arrrgh! I think he ran out over the course of the day and by night he was off balance and overly GABA inhibited again.

Can't get Away From DYRK1A

I found this picture. Wow! Look at how many things are affected by DYRK1A.
I recommend reading the journal article where I got this. You can download the picture from the journal into a power point slide and then it is clear. Link

We talked about Tau, App and NFATc but did not even define the rest.
It is amazing how many items 1 gene can affect. Unbelievable!!

A Little History Lesson

I thought it was time for a little history lesson for all the newbies to the DS world. In 1997, Neal was born-I'm dumped into the DS world without any notice. All of a sudden, the internet is something I need. I bought a laptop and dialed up the internet. Can you imagine? how slow could we go......
Research started. I found the library.....pubmed.
Then I found forums where people talked to each other. So, I joined and began to participate. Soon, it became very apparent that there was a lot of bickering going on. Actually, is was down and dirty verbal fighting. Do you know what people were fighting about? Whether or not DS should take vitamins. Are you kidding? We have one of the most complex genetic conditions and people are arguing about vitamins!

I soon walked away from the forums and continued to read the science. A small group of us about 10 emailed each other what we found in the scientific studies. The pace of the research was slow. We wanted something now and it wasn't until 2004 that Stanford published the study about the GABA antagonist. Then, it wasn't until Feb. 2005 that we found ginkgo biloba. Luckily for Neal an avalanche of information came out, compared to the first half of his life. The rest of the Changing Minds Protocol came about in 2006 and 2007. We may not know everything and there is still a long way to go but yesterday I came home and he had written this paragraph with his tutor. I called her this morning to make sure he had done it himself. She said, of course. Tomorrow, I will list all that he is now taking because we have added to the protocol.



Something Good to Share

Yesterday, Neal came home with a Valentine's that he colored for me and he colored a dragon. The dragon is his new pet but I was so impressed with his coloring. A couple of things have improved: 1) he used 4 different colors [usually he only uses 1 color] 2) he stayed in the lines. I scanned it in.
This is central and detailed vision. He keeps improving daily! [one little brag]

Web Conference - Feb. 17, 2011 at 7 PM

Down Syndrome Achieves is a Down syndrome organization pushing for more NIH funding for DS research. It would be great if we came out in force to show our support. There is good information available with the little funding DS has had....... but imagine the possiblities.
The squeaky wheel gets the grease!!! Let's squeak!!

 LIVE Web Conference:
The Abandonment of DownSyndrome Research


Thursday, Feb. 17


7PM

Next Thursday, Feb. 17, at 7PM, nearly 100 families from as far away as CA, AL, VA, WI, SD, IL, FL, TX, OK, MN, WA, OR, and other states across the country will participate in our LIVE web conference: The Abandonment of Down Syndrome Research.
Whether we choose to acknowledge it or not, constant failures in Down syndrome research affects us all and prevents us from achieving the type of future that we all hope for our loved ones with DS.
This web conference will not be easy for anyone who loves someone with DS. It is a cold hard anguishing look at why DS research has failed for more than 100 years to make breathrough discoveries that would vastly improve the quality of life and health for all of our infants, toddlers, teens and adults swith DS. But there is a way forward...
Take 6o-minutes to learn the facts, and learn more about how and why your help is needed to turn this disastrous trend around. As a parent, grandparent or advocate, I urge you to please join the web conference as well. I hope you will take the time to join us. Click here to register now!
Lito Ramirez
Founder of Down Syndrome Achieves

EGCG, DYRK and Folate ie. green tea, increased gene and a B vitamin... Kinda.....

I took a minibreak from DYRK1A etc. But it is time to think about it again. Andi commented below about green tea and folate and I was getting to that but it involves another pathway.........Methylation.

Methylation is a very important basic process in the body. In the late 1990's Neal and his buddies with DS sent their blood to a researcher named Dr. Jill James. She discovered that the methylation pathway is disturbed in DS (and in us Moms) because some of the enzymes in the pathway are overexpressed. It is easier to look at a diagram than just to write about it.

Here is an overview of the Methylation Pathway. We are going to talk about the 2 things in red. In the middle of the diagram is CBS (cystathione beta synthase). This enzyme is triplicated on the 21st chromosome which presumably pulls that pathway down.
The second scratchy red is 5-CH3 THF - which is methyl tetrahyrdrofolate.
Have you have heard of folic acid? It is added to every cereal. "Fortified with Folic Acid".

There is a very knowledgable website called Super Down Syndrome that has a terrific explanation about many topics. But one is an explanation about folic acid versus folinic acid.
"...medical professionals still haven’t figured out that folic acid is not the same as the naturally occurring vitamin folate.

Folic acid is a single type of molecule, crystallized in 1943 by a scientist working for the patent medicine company Lederle Laboratories, then a subsidiary of American Cyanamid Corporation. Folic acid is the fully oxidized form of naturally occurring folates, which are found in leafy and green vegetables......

Folate was originally isolated from brewer’s yeast and spinach in the 1930s. Once isolated and exposed to air it becomes unstable and breaks down, and is generally no longer useful in nutrition. But a small amount of natural folate can be transformed by oxidation (a natural process) into folic acid, a much more stable form with a very long shelf life.
While human and animal cells cannot use the folic acid molecule itself in their normal metabolic processes, human cells (principally the liver) can transform folic acid back into many of its metabolically useful folate forms. That’s why folic acid—despite not being found in food—can do so much nutritional good, the best-known example being the prevention of birth defects including spina bifida, cleft lip, and cleft palate."
But what if your population cannot utilize folic acid? It is necessary to supplement with the more active form folinic acid which translates to 5-methyl tetrahydrofolate. Sound familiar? It is the folate in the cycle.

 Neal and I for that matter supplement with Folinic acid.

OK here comes the complication from green tea extract and folates. Green tea reduces an enzyme (DHFR) [orange] that converts folic acid tetrahydrofolate in one direction - here is another diagram:

But I now think that the DYRK1A is sufficiently dangerous that it is worth turning it down and then supplementing with a good form of folate. It is important to add B12 (green) as well. You didn't think this was going to be easy did you? The medical profession has thrown their collective hands up for years saying Down syndrome is too complicated to treat. They continue to say there are too many things wrong. True enough. But I think we can unpeel this syndrome like an onion. Don't get discouraged that there is another layer. Be prepared there are more layers to come.
We will look more closely at these pathways because there are more complications than we have discussed today.

Choline Part 2

Tomorrow we will get back to the green tea extract and DYRK1 A gene because there are more issues to discuss but today let's look at one little study that showed positive results for the Down syndrome mouse.
Here is the study abstract:
Behav Neurosci. 2010 Jun;124(3):346-61.


Perinatal choline supplementation improves cognitive functioning and emotion regulation in the Ts65Dn mouse model of Down syndrome.
Moon J, Chen M, Gandhy SU, Strawderman M, Levitsky DA, Maclean KN, Strupp BJ.
Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.

Abstract

In addition to mental retardation, individuals with Down syndrome (DS) also develop the neuropathological changes typical of Alzheimer's disease (AD) and the majority of these individuals exhibit dementia. The Ts65Dn mouse model of DS exhibits key features of these disorders, including early degeneration of cholinergic basal forebrain (CBF) neurons and impairments in functions dependent on the two CBF projection systems; namely, attention and explicit memory. Herein, we demonstrate that supplementing the maternal diet with excess choline during pregnancy and lactation dramatically improved attentional function of the adult trisomic offspring. Specifically, the adult offspring of choline-supplemented Ts65Dn dams performed significantly better than unsupplemented Ts65Dn mice on a series of 5 visual attention tasks, and in fact, on some tasks did not differ from the normosomic (2N) controls. A second area of dysfunction in the trisomic animals, heightened reactivity to committing an error, was partially normalized by the early choline supplementation. The 2N littermates also benefited from increased maternal choline intake on 1 attention task. These findings collectively suggest that perinatal choline supplementation might significantly lessen cognitive dysfunction in DS and reduce cognitive decline in related neurodegenerative disorders such as AD.


PMID: 20528079 [PubMed - indexed for MEDLINE]PMCID: PMC2955960 [Available on 2011/6/1]

They supplemented with choline which crosses the Blood Brain Barrier (protective barrier for the brain) with a transport system. Phosphatidylcholine (PC) passes through the BBB because it  is fat soluble. I'm always thinking about making it as easy as I can for the body. So, my choice of supplementation is PC as opposed to free choline.

Choline

I was reading about choline and thought this is a good break from the genes.
Choline is not exactly a vitamin but it is an essential nutrient. We can make a small amount of it but it must be eaten regularly. The Linus Pauling Institute has a terrific write up explaining choline and its functions. They state:

  The majority of the body's choline is found in specialized fat molecules known

 as phospholipids, the most common of which is called phosphatidylcholine or lecithin . (1)

I bolded the phosphatidylcholine for emphasis. Choline is a very important nutrient.

It is involved in these 5 ways:

• Structural integrity of cell membranes
• Cell signaling
• Nerve impulse transmission
• Lipid (fat) transport and metabolism
• Major source of methyl groups

 Let's look at the structure of the cell membrane. Cell membranes are called a bilayer because they are formed from a double layer of fats and phosphate heads.
The green inside are the fats and the pink balls are the phosphate heads. Choline is essential in the formation of phospholipids ie cell membrane.  The liver alone has ~ 300,000 square feet of membrane.
That is more than 4 football fields!
A great article on Phosphatidyl choline that explains the membrane in more detail is on the BodyBio website.

The second major function is cell signalling. If you put cell signalling into google image, it will blow your mind. It is soooooo complex.  Here is a good picture of one type of cell signal. Notice it occurs next to the membrane.

 

Nerve Impulse Transmission is the neurotransmittors like acetylcholine. These are the chemical messangers that jump from one nerve to the next.

 Phosphatidylcholine is a required component of fat transportation and processing. Without adequate phosphatidylcholine, fat and cholesterol accumulate in the liver.

Choline is a major source of methyl group which is a carbon and 4 hydrogens. We will come back to this because it is very important in Down syndrome.

Needless to say. Choline is critical for good health and function. It is found in beef and eggs, for example.

 Food Serving Total Choline (mg)

Beef liver, pan fried 3 ounces* 355

Wheat germ, toasted 1 cup 172

Egg 1 large 126

Atlantic cod, cooked 3 ounces 71

Beef, trim cut, cooked 3 ounces 67

Brussel sprouts, cooked 1 cup 63

Broccoli, cooked 1 cup, chopped 62

Shrimp, canned 3 ounces 60

Salmon 3 ounces 56

Milk, skim 8 fl oz. 38

Peanut butter, smooth 2 tablespoons 20

Milk chocolate 1.5-ounce bar 20



*A three-ounce serving of meat or fish is about the size of a deck of cards. (1)






 

Review Again and Again and Again

Whew!! These blogs have been a lot of science. If you are still with me, let's review.
3 Players:
These genes are at a triple dose in Down syndrome:

1. DYRK1A
2. RCAN or (DSCR1)
3. APP

DYRK1A is triplicated (3X) in Down Syndrome and is involved in cell growth and development.

• decrease brain volume (slows cell growth and development)
• decreases synaptic plasticity [decreases BDNF (Brain Derived Neurotrophic Factor)- like brain food]
• increases the production of the toxic amyloid beta plaque
• hyperphosphoralates tau protein which is a structural protein inside the nerves. The tau protein falls off the internal structure leading to collapse of the nerve

RCAN or (DSCR1)

• decreases cell growth and therefore brain volume
• the DSCR stands for Down Syndrome Critical Region. It has since been renamed to RCAN

APP stands for Amyloid Precursor Protein

• 3 enzymes cut this protein in different spots
•  the DYRK1A changes the APP and sets it up to be cut in a toxic manner creating the poisonous amyloid beta plaque.
• The amyloid beta plaque is hallmark of Alzheimer's and Down syndrome brain pathology
• in a mouse model, 3 times APP alone does not show the same pathological changes seen in Down syndrome
• in a mouse model, 3 times APP and 3 times DYRK1A does resemble the brain changes seen in Down syndrome. Also, these mice have similar learning deficiencies seen in Down syndrome.

What can we do to help turn down these genes? Well obviously we need to rebalance the system if we can.

One thing came up over and over in the journal articles. GREEN TEA EXTRACT

Green Tea Extract decreases the expression of the DYRK1A gene.

So, if DYRK1A was expressed at a more normal level, the person with Down syndrome should be able to grow nerve cells and therefore normalize brain volume. Learning and memory should increase with more synaptic plasticity. Forming less amyloid beta plaques should at least delay the onset of toxic plaque build up in the brain. And, structurally, the tau protein should stay more normal therefore, less nerve cells will collapse.

Another journal article, found that ANTIDEPRESSANTS decrease the expression of the RCAN gene. There were some contradictory studies on this point but ANTIDEPRESSANTS also are known to increase BDNF which is probably a good thing in Down syndrome.

Thanks for the comments on facebook. I know this is tough stuff but you don't have to know every detail. You need to understand the overall pathology that is an ongoing problem in Down syndrome. 'WE CAN' help our loved ones with Down syndrome. It is like an onion one layer at a time.

Samples of Neal's work

I will continue with the science tomorrow..... but I wanted to take a break and share some of Neal's school work with you all.  My son, Neal, is 13 years old.  He has Down syndrome and he has been on the CMF protocol since he was 8 years old, so about 5 years.  Below are some samples of his work with a description or explanation for each.

Here, he did a unit on Clara Barton.  There is more to the story, but I only included one page of reading material so you could see the level.  He did this work himself.

    

















This one is from a workbook at grade 4-5 level.  On the first page, Neal has to decide if the pairs of words are synonyms, antonyms or homonyms.  He got them all right!  The next page, he had to choose a fairy tale he liked and write sentences about how the story begins, what happens in the middle and how it ends.  He also answered a crossword puzzle without having the list of words.  I thought it was very good!