Drug Improves Cognitive Function in Mouse Model of Down Syndrome

This was posted on the DSTNI listserv by Richard and I thought I'd share here:

Drug Improves Cognitive Function in Mouse Model of Down Syndrome

July 2, 2013 — An existing FDA-approved drug improves cognitive function in a mouse model of Down syndrome, according to a new study by researchers at the Stanford University School of Medicine.

The drug, an asthma medication called formoterol, strengthened nerve connections in the hippocampus, a brain center used for spatial navigation, paying attention and forming new memories, the study said. It also improved contextual learning, in which the brain integrates spatial and sensory information.

Both hippocampal function and contextual learning, which are impaired in Down syndrome, depend on the brain having a good supply of the neurotransmitter norepinephrine. This neurotransmitter sends its signal via several types of receptors on the neurons, including a group called beta-2 adrenergic receptors.

"This study provides the initial proof-of-concept that targeting beta-2 adrenergic receptors for treatment of cognitive dysfunction in Down syndrome could be an effective strategy," said Ahmed Salehi, MD, PhD, the study's senior author and a clinical associate professor of psychiatry and behavioral sciences. The study will be published online July 2 in Biological Psychiatry.

Down syndrome, which is caused by an extra copy of chromosome 21, results in both physical and cognitive problems. While many of the physical issues, such as vulnerability to heart problems, can now be treated, no treatments exist for poor cognitive function. As a result, children with Down syndrome fall behind their peers' cognitive development. In addition, adults with Down syndrome develop Alzheimer's-type pathology in their brains by age 40. Down syndrome affects about 400,000 people in the United States and 6 million worldwide.

In prior Down syndrome research, scientists have seen deterioration of the brain center that manufactures norepinephrine in both people with Down syndrome and its mouse model. Earlier work by Salehi's team found that giving a norepinephrine precursor could improve cognitive function in a mouse model genetically engineered to mimic Down syndrome.

The new study refined this work by targeting only one group of receptors that respond to norepinephrine: the beta-2 adrenergic receptors in the brain. The researchers began by giving mice a compound that blocks the action of beta-2 adrenergic receptors outside the brain. They then gave the mice formoterol, a drug that can partially cross the blood-brain barrier and that was already known to activate beta-2 adrenergic receptors. Because people with Down syndrome are prone to heart problems, the researchers avoided activating a different group of norepinephrine-sensitive receptors, the beta-1 adrenergic receptors, which predominate in the heart.

The scientists saw improvement on a standard test of contextual learning in mice. In contextual learning, the brain integrates sensory and spatial information to remember the layout of a complex environment: for instance, a person using sounds, smells and sights to remember the location of a store in a shopping mall is using contextual learning. The researchers also saw more synapses and a more complex structure of dendrites, the nerves' outgoing ends, in the hippocampus after the affected mice received formoterol.

"The fact that such a short period of giving medication can make these neurons much more complex is very interesting," Salehi said, noting that mice in the study received the drug for a maximum of two weeks.

Further tests will be needed to determine whether formoterol might be an appropriate treatment for people with Down syndrome or whether to use another drug that activates the same receptors, Salehi said. The dose used in this study was many times higher than that used for asthma treatment, he cautioned, so it is not known whether it is safe. A lower dose might work, or other drugs that affect beta-2 adrenergic receptors might be safer and more effective in humans. Researchers also want to explore what parts of learning -- taking in new information, remembering it or both -- are affected by the drug treatment.

Prior research to improve cognitive function in children with Down syndrome has sometimes raised concerns from families that cognitive treatments would alter positive attributes of these children's personalities, but Salehi said that is not the goal of his team's research.

"Our aim is to enable these children to do better in school," Salehi said. "It is absolutely not to change their personalities or the way they react to society." Changing a child's personality would be much more complicated than activating a subgroup of receptors in the brain, he said.

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Jumpy Monkey Coffee - Helping Individuals with Disabilites Get A Job

This came across the Einstein-Syndrome listserv last week and I thought I'd share:

On Hatteberg's People, creating a meaningful and enriching life for the developmentally disabled is the goal of a non-profit company called Mosaic in Winfield. In a unique relationship, they are partnering with local businesses to enrich the lives of the Mosaic clients, and the key is.... coffee.

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Young Man with Down Syndrome Gets His Driver's License - John Marrs

I've posted a few times about John Marrs, via updates from his mom, Jenny, over the years. John has recently graduated highschool and is now going to a local college. This is the most recent update which his mom shared:

John went into the DMV and took his driver's test yesterday. In IL a student starts driver's training as a 15 year old. You must pass the written portion of the IL test before you get your permit to drive with an adult, which John did. Then, if the driver's ed teacher sees fit, the student is given a license following his 16th birthday. Our teacher was not our best friend. So, John had to wait until after he was 18 to test at the DMV. We finally got around to taking him in yesterday for his driver's test. When he returned from his drive, I was told, "he is amazing!" John is now a licensed driver!

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It's Not A Choice. It's A Baby Who Just Happens To Have Down Syndrome.

Every few months I get a call from someone who either has just received a diagnosis of Down syndrome for their baby or is just finding out about TNI.

Yesterday I received a call from a mother who is just a few months along in her pregnancy and had received a prenatal diagnosis of Down syndrome for her unborn baby. I had a good, long conversation with her about what she can do for her baby.

But, some of the conversation dealt with the diagnosis, since it was still so fresh for her. She was discouraged because of the lack of support she had received and the comments to which people hinted towards abortion. She shared she had always been pro-life, so she was keeping her baby. But, I couldn’t sit here and be quiet over one of the comments she shared. I completely understand why she would be discouraged by the comments she has received.

She shared that one of her co-workers had said, "I'm so sorry! That is one of the worst things that could ever happen to you!"

*sigh*

People need to stop and think about what they are saying. This mother is in the very small percentage – 8% - of families who keep their baby after a prenatal diagnosis of Down syndrome. Yes, that’s right, 92% of babies prenatally diagnosed with Down syndrome have their hearts stopped by abortion and are thrown away as if they are not human.

People act like it’s the end of the world to have a child with Down syndrome. Really, folks, when that child is born, it is just.a.baby. That baby, has eyes, ears, a nose, a mouth, hands, feet, legs, arms, just like you and me. It’s a human. That baby wants to be held and loved by its mother as every other newborn does. That baby needs love and care. It needs its diaper changed. That newborn depends on its mother just like every other baby born does, for love, care, nourishment, protection and its voice. You or I could’ve been born with a third chromosome. That child did not choose to have a third 21st chromosome. God chose to give that child an extra chromosome. It’s time to lighten up, start loving, have compassion on that unborn life, be that baby’s voice and realize that all children are a blessing.

You know what, just because someone might take life a little slower, doesn’t justify ending that baby’s life. It can be a good thing to slow down and appreciate the small things in life more.

Sure, there are health concerns that are associated with Down syndrome. The concern for that is understandable, but does that justify snuffing out that little one’s life? To kill a helpless life that cannot speak for itself? No, it’s time to help that child and be that child’s voice, to protect and care for that baby.

Someone can end that life within their womb because of a diagnosis of a third chromosome. But, it’s not justified, it is wrong and they will be held accountable for their acts. God gave that mother a gift. It’s not a choice. It’s a life. It’s a child. It’s a helpless baby.

I look at my brother and see what a huge blessing he has been from the moment he was born. I cannot even begin to fathom how someone could be so cold to kill (abort) such a helpless life, who had nothing to do with having an extra chromosome. Society has promoted that it’s the “mother’s choice”, but no one seems to remember that there is a baby inside of that womb who is a person. Where is that baby’s choice?

Instead of falling into the 92% of families who abort their babies who are prenatally diagnosed with Down Syndrome, I beg any expectant mothers who run across this blog, to protect that baby who is prenatally diagnosed and be a voice for that baby.

Let's celebrate this baby, who just happens to have a diagnosis of Down syndrome, and sing its birthday song when it's born. Instead of being another birthday song that is unsung, because a child was thrown away, torn up and had its heart stopped. Simply because someone didn’t have the love to care for a child who was a little different.

As I sit here and type through the tears, I realize this post may upset some people, but I will not apologize for speaking up for those babies whose hearts are stopped at the hand of violence, and who suffer for wrong, cloaked in the name of ‘choice.’  I’m not afraid to speak up for the unborn babies who have their bloodshed and are torn up by such a shameful, heartless act. Because it’s not her choice, therefore I will not keep silent.

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DYRK1A Overexpression Linked to Hypothyroidism

Green Tea Extract, EGCG, is a safe DYRK1A inhibitor. Which is one of the many reasons EGCG is so beneficial for people with DS.

Well, a new study is out which shows the overexpressed DYRK1A gene being linked to hypothyroidism in Down syndrome. Read below:

Dyrk1A (dual-specificity thyrosine (Y)-phosphorylation regulated kinase 1A) overexpression is linked to congenital hypothyroidism in Down syndrome

http://www.endocrine-abstracts.org/ea/0029/ea0029p1609.htm



D. Kariyawasam1, M. Martin-Pena1, L. Rachdi1, A. Carré5, M. Houlier1, C. Dupuy5, N. Janel4, J. Delabar4 & M. Polak1,2,3

Introduction: Trisomy 21 or Down Syndrome (DS) patients have a predisposition for Congenital Hypothyroidism which can aggravate their mental status.

Hypothesis: The presence of three copy of Dyrk1a gene, localized in chromosome 21 in Humans, is responsible for a thyroidal dysgenesis.

Our aim is to understand the molecular mechanisms underlying this condition.
Methods: The transgenic Dyrk1a (TgDyrk1a) mouse, our DS murine model, contains three copies of the Dyrk1a gene and was obtained through electroporation of a Bacterial Artificial Chromosome containing the entire gene with its own regulatory sequences. We studied their thyroidal phenotype in young adults (8–13 weeks old) by histology, immunohistochemistry and blood T4 hormonal dosages, reflecting the thyroidal function. We compared the thyroidal molecular phenotype of the TgDyrk1a and wild type mice: RNA levels of molecules involved in the thyroidogenesis were studied by qRT-PCR at different embryonic stages.

Results: The average surface of thyroidal follicles in young adult TgDyrk1a mice is smaller (TgDyrk1a: 2164 μm2 versus wild type: 1420 μm2; P=0.005; n=6). They presented also a lower plasmatic T4 (TgDyrk1a: 2.4 ng/ml versus wild type: 3.7 ng/ml; P=0.019; n=14). The overexpression of Dyrk1a in the thyroids leads to an elevation of RNA level expression of Nkx2-1, Foxe1, Thyroperoxidase and Thyroglobulin, involved in thyroidogenesis, at E13.5 and E17.5.
Conclusion: Our first results show an abnormal thyroid function and histology in young adult TgDyrk1a mice and an overexpression of thyroidal developmental molecules. To further understand the molecular mechanism linking Dyrk1a overexpression to altered thyroid folliculogenesis and function we are studying some candidates as direct targets of Dyrk1a using thyroidal cell lines.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported. Supported by Sandoz SAS, EDF and the Fondation Lejeune. T4 dosage courtesy of Pr S Refetoff, Chicago.



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Full Text of EGCG Study on Mitochondrial Biogenesis in Individuals with Down Syndrome

Remember the study that prompted my big post on EGCG a few months back? The one that showed EGCG can actually create Mitochondrial Biogenesis in individuals with Down syndrome? Yeah, that was huge news!

Epigallocatechin-3-gallate prevents oxidative phosphorylation deficit and promotes mitochondrial biogenesis in human cells from subjects with Down's syndrome

The abstract of that study is below:

A critical role for mitochondrial dysfunction has been proposed in the pathogenesis of Down's syndrome (DS), a human multifactorial disorder caused by trisomy of chromosome 21, associated with mental retardation and early neurodegeneration. Previous studies from our group demonstrated in DS cells a decreased capacity of the mitochondrial ATP production system and overproduction of reactive oxygen species (ROS) in mitochondria. In this study we have tested the potential of epigallocatechin-3-gallate (EGCG) – a natural polyphenol component of green tea – to counteract the mitochondrial energy deficit found in DS cells. We found that EGCG, incubated with cultured lymphoblasts and fibroblasts from DS subjects, rescued mitochondrial complex I and ATP synthase catalytic activities, restored oxidative phosphorylation efficiency and counteracted oxidative stress. These effects were associated with EGCG-induced promotion of PKA activity, related to increased cellular levels of cAMP and PKA-dependent phosphorylation of the NDUFS4 subunit of complex I. In addition, EGCG strongly promoted mitochondrial biogenesis in DS cells, as associated with increase in Sirt1-dependent PGC-1α deacetylation, NRF-1 and T-FAM protein levels and mitochondrial DNA content.

In conclusion, this study shows that EGCG is a promoting effector of oxidative phosphorylation and mitochondrial biogenesis in DS cells, acting through modulation of the cAMP/PKA- and sirtuin-dependent pathways. EGCG treatment promises thus to be a therapeutic approach to counteract mitochondrial energy deficit and oxidative stress in DS.

Well, we have the full text in PDF format of that study, which is always a helpful resource to have. You can download the PDF here.



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Wordless Wednesday: Bunny Love n' Cuddles

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New Randomized Double-Blind Trial in the Works With EGCG

Richard over at the DSTNI listserv, shared the following:

I just found out that a second and larger clinical trial has started in Spain. The dosage remains the same as in the pilot study, but this time the duration was set for 12 instead of only 3 months, and there are 100 participants ages 14 to 29yrs. First results are expected for December 2013.

The name of the clinical trial is: Normalization of dyrk1A and APP Function as an Approach to Improve Cognitive Performance and Decelerate AD Progression in DS Subjects: Epigallocatechin Gallate as Therapeutic Tool.

This is the brief summary and the goal of the study:

Epigallocatechin-3-gallate (EGCG), the major catechin in green tea, is postulated to modulate dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) and amyloid beta precursor protein (APP) gene overexpression in the brains of Down syndrome mouse models. The clinical study is aimed at demonstrating that normalization of Dyrk1A and APP functions is a therapeutic approach to improve cognitive performance and decelerate AD (Alzheimer's disease) like progression.

You can see the full clinical trial page at http://clinicaltrials.gov/ct2/show/record/NCT01699711.


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Betty Crocker Gluten Free Baking Mixes & Gluten-Free Dixie Spice Cake with Caramel Frosting

MyBlogSpark provided us with a baking gift set, complete with a pan, rolling pin, a couple rubber utensils and a timer to be able to do a blog post on Betty Crocker's Gluten Free Baking Mixes.



So, we went out and picked up a Betty Crocker Gluten Free Pancake and Baking Mix. This mix is your all-in-one gluten free flour combination and it works great. We found a regular cake recipe and changed it up some to fit what we needed and so that it would be gluten-free.

Delicious, classic — and Gluten Free!

Now, Gluten Free baking gets even easier (and tastier!) with two all-new additions to the delicious line of Betty Crocker Gluten Free baking products — introducing Gluten Free Sugar Cookie mix and All-Purpose Gluten Free Rice Flour Blend.

Smart moms already trust the great taste of Betty Crocker Gluten Free Brownie, Cookie and Cake mixes that the whole family can enjoy, and now beginner-to-expert bakers can use mixes or create from scratch delicious recipes year-round!

So why are Gluten Free moms choosing Betty Crocker?

•    Taste — Our consumers rave about the great taste of our Gluten Free products. Check out some of the great comments here.
•    Shareable — You can make one dessert for the whole family.
•    Normalcy — You can feel "normal again" baking for your family just like before you went gluten free.

The cake we chose to make was a spice cake. Here's the recipe below. Enjoy! (Remember you can always click the "Printer Friendly" button at the bottom of each blog post to print the recipe out)

Gluten-Free Dixie Spice Cake with Caramel Frosting

Ingredients:

Cake:
2 1/4 Cups Betty Crocker Gluten Free Baking Mix
1 1/4 cups firmly packed brown sugar
1/2 cup sugar
1/2 teaspoon allspice
1/2 teaspoon cinnamon
1/8 teaspoon clove powder
1 cup milk
2/3 cup coconut oil*
1 teaspoon vanilla
3 eggs

Frosting:
1/2 cup coconut oil or butter
1 cup firmly packed brown sugar
1/4 cup milk
3 cups powdered sugar
1/2 teaspoon vanilla

Directions:

1. Preheat oven to 350 degrees. 

2. Combine all the cake ingredients.

Stir until well moistened and mixed together.

3. Grease your pan(s). Because this recipe makes a 13"x9" cake, we used two 8"x8" pans.

4. Fill the pan with the batter - about 1/2 full.

5. Bake in 350 degree oven for 30-45 minutes or until toothpick inserted comes out clean and the edges are a light golden brown.

6. For the frosting: In medium saucepan, melt coconut oil or butter. Add brown sugar, cook over low heat for 2 minutes, stirring constantly. Add milk, continue cooking until mixture comes to a rolling boil. Remove from heat. Gradually add powdered sugar and vanilla, mix well. If needed, add a few drops of milk for desired spreading consistency. Spread over cooled cake.

Because I was baking with a friend of mine who is 6 years old, we added some food coloring to the frosting to give it a purple hue. We also topped our cake with Toffee Pieces.

Be sure to visit the Betty Crocker website, "like" Betty Crocker on Facebook, and follow Betty Crocker on Twitter.

The information and prize pack have been provided by General Mills through MyBlogSpark.

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