Neuron Finding Lifts Hopes for Down Syndrome Drug

from Joan Arehart-Treichel, Psychiatric News:

Discovering a dearth of acetylcholine and norepinephrine in the hippocampus of a mouse model of Down syndrome opens promising therapeutic avenues for people with the disorder.

Down syndrome is usually due to each cell in the human body having three copies, rather than two copies, of chromosome 21. This heartbreaking illness leads not just to a spate of physical abnormalities and cognitive dysfunction, but often to early-onset Alzheimer’s disease.

A pivotal brain region affected by Down syndrome is the hippocampus. Now scientists at Stanford University School of Medicine have made two important findings about what occurs in that region in a mouse model of Down syndrome, which purportedly translates to people with the syndrome.

 

One is a loss of two types of neurotransmitter-producing neurons in the hippocampus—acetylcholine-producing neurons and norepinephrine-producing neurons. The other is that this loss is linked with the overexpression of the amyloid precursor protein gene in the hippo-campus. Mutations in this gene, which is located on chromosome 21, are known to lead to early-onset Alzheimer’s, and it may be that early onset of Alzheimer’s pathology in people with Down syndrome is due in part to overexpression of the amyloid precursor protein gene.

 

These findings have provocative therapeutic implications for people with Down syndrome, the scientists also pointed out online September 27 in Biological Psychiatry. For instance, although the amyloid precursor protein gene should be a primary therapeutic target in Down syndrome, there are no safe and effective medications on the market to reduce the gene’s expression. In contrast, since a paucity of norepinephrine-producing neurons in the hippo-campus also seems to contribute to Down syndrome, medications that enhance norepinephrine levels in the brain and are already on the market to treat attention-deficit/hyperactivity disorder might be of therapeutic benefit to individuals with Down syndrome.

 

Moreover, such medications might also subdue the action of the amyloid precursor protein gene in such individuals, they speculated.

 

“We are indeed working on this group of drugs—drugs that are able to increase norepinephrine levels and that have already been approved by the Food and Drug Administration—in our mouse models,” Ahmad Salehi, M.D., Ph.D., a clinical associate professor of psychiatry at Stanford and the study’s senior investigator, told Psychiatric News. “This strategy could speed up the development of a treatment for cognitive function in Down syndrome enormously.”

 

The scientists’ discovery of a paucity of acetylcholine-producing neurons in the hippocampus of an animal model of Down syndrome holds therapeutic promise, the researchers noted. In fact, other researchers reported eight years ago that the Alzheimer’s drug donepezil, which slows the break down of acetylcholine in the brain, might improve cognitive scores and expressive language in children and adults with Down syndrome.

 

Yet if donepezil improves cognitive function and language in these individuals, is there reason to believe that medications that increase norepinephrine would be superior to donepezil in that regard? Asalehi believes there is. “I think using norepinephrine-ergic drugs would be far superior to cholinergic ones for the following reasons: The norepinephrine system has some regulatory effects on the cholinergic one. It has been shown that lesions in the former lead to increased severity of cholinergic deficits; most adults with Down syndrome will show Alzheimer’s-related pathology, particularly amyloid plaques. There are new studies showing that increasing norepinephrine levels in mouse models of Alzheimer’s significantly reduce amyloid accumulation. These findings suggest that using norepinephrine-ergic drugs might not only restore cognition in kids with Down syndrome, but also reduce Alzheimer’s-related pathology in adults with the syndrome.”

 

“Studies such as this one help to further our overall understanding of central nervous system function and in particular differences seen in individuals with Down syndrome,” Melanie Manning, M.D., director of the Center for Down Syndrome at Stanford’s Lucile Packard Children’s Hospital, told Psychiatric News.

 

“Many of the families of individuals with Down syndrome follow results from research studies such as this one with great interest. They express a desire to learn more about potential clinical applications that lie ahead.”

 

The research was funded by the Mental Illness Research, Education, and Clinical Center Department of Veterans Affairs; Down Syndrome Research and Treatment Foundation; Thrasher Foundation; and Alzheimer’s Association.

 

Ahmad Salehi, M.D., Ph.D.: 

 

An abstract of “Neurobiological Elements of Cognitive Dysfunction in Down Syndrome: Exploring the Role of APP” is posted at <www.biologicalpsychiatryjournal.com/article/S0006-3223(11)00822-5/abstract>.

Down syndrome and Alzheimer's

from newstimes.com:

Dear Readers,

I would like to stray from our regular pattern of answering one of your emails or letters. The reason for this is a particular topic which many of you brought up during a recent lecture given by geriatrician Marina Blagodatny and psychiatrist Neil P. Dolan at the Trumbull Marriott.

The topic in question was dementia, specifically Alzheimer's dementia in people with Down syndrome. I hope that you do not mind my taking the opportunity to write about it some more.

Let's start with the definition of Down syndrome. It is a genetic disorder affecting one in 733 live births and accounts for about 15 percent of intellectual disabilitiy cases.

Symptoms of the learning problems associated with the syndrome range from mild to moderate, as does the patient's functional capacity. The cause of this disorder is, most of the time, an extra chromosome -- or genetic "building block" -- in our body. Chromosome 21 is the one affected. Normally a person has two copies of each of the chromosomes.

In at least 90 percent of Down syndrome cases, a person has three copies of Chromosome 21. This is not an illness one inherits from a parent, at least not in a majority of cases. The most commonly known risk factor is late maternal age. By age 45, a woman's risk of having a baby with this disorder is one in 35.

Life expectancy of patients with Down syndrome has increased dramatically in the last century. From roughly 10 years in the 1920s, it is now quite normal for those with Down syndrome to enjoy life way beyond age 50.

Unfortunately, there are many problems these patients and their families have to struggle with throughout their lives. People born with the syndrome age faster, and are prone to developing dementia.

It is known that 25 percent of Down syndrome patients have dementia by age 35. They are three to five more times more likely to get dementia as compared to patients the same age not born with the genetic disorder.

What is most perplexing is the fact that, although virtually all adult patients with Down syndrome have specific changes in the brain characteristic of dementia, not all of them have the symptoms.

For those of you who are more scientifically inclined, the changes are called neurofibrillary tangles and amyloid plaques, as well as loss of nerve cells in certain parts of the brain.

It must be clarified that people with other forms of intellectual disability not related to Down syndrome have the same risk and rate for dementia diagnosis as the non-affected population.

Scientists still do not fully understand why this is the case, other than that the Chromosome 21 abnormalities must play a significant role. Alzheimer's disease is the most common form of dementia. It is a progressive memory disorder that affects our ability to reason, remember, use language and think.

The disease can attack quickly and lead to demise in only a few years, or linger over 10 to 15 years, affecting not only the patient but the whole family. Approximately 4 million Americans are affected today by Alzheimer's. Presentation of the disease in patients with Down syndrome is quite different from that in other dementia patients.

Loss of language skills and the ability for self-care are quite common early. Seizures happen often in individuals who did not have them before. Incontinence, personality changes and sleep disruptions are also seen.

Since the mental abilities of patients with Down syndrome vary greatly to begin with, diagnosis of dementia is challenging. Unfortunately, the majority of patients are diagnosed late in the process of the illness. Standardized tests used in non-Down syndrome individuals do not apply to this group.

It is crucial for a specialist involved to have some idea of the person's cognitive baseline. Many advocate for the universal screening of Down syndrome individuals around age 30. There is a questionnaire called "The Dementia Questionnaire for Mentally Retarded Persons," which can help, as well as a few other available tools. As a rule, a specialized dementia center is the best place to follow a patient with Down syndrome and Alzheimer's. The input from the caregivers and the primary care physician are considered absolutely necessary for the proper diagnosis and the meaningful follow-up.

One of the important goals of early diagnosis is to rule out other reasons for cognitive decline and behavioral problems that can be potentially curable. Thyroid problems, excessive medication use, severe depression, and unrecognized hearing and vision problems may all present as similar or identical to Alzheimer's. Even simple infection can trick us.

The treatment of Alzheimer's dementia in Down syndrome patients is uncharted waters. Only one out of four drugs available has been tested in these patients, and no drug is specifically approved by the Food and Drug Administration. Trying them, however, may prove very beneficial, as they may help with behaviors and stabilize functional abilities.

Other medications, like antidepressants, mood stabilizers and anti-anxiety medications, may also play a role when used judiciously and closely supervised and monitored.

There is yet another reality of this particular scenario. Many primary caregivers of Down syndrome patients in their 40s and 50s can be their aging parents and/or siblings. Not only do they have to face their own fears about forgetfulness and their own memory lapses, they are often unable to meaningfully plan ahead.

Legal issues are important, as well as financial ones. There has to be a plan of care in case of a caregiver's illness or, as horrible as it is to think about, death.

I strongly recommend that all involved use their local Alzheimer's Association, as well as local Down syndrome support groups and the National Down Syndrome Society. The help of local religious organizations also can be priceless. Government support is available, albeit limited. All of us professionals involved in diagnosis and treatment of dementia are more than willing to help.

Dr. Beata Skudlarska is a Bridgeport geriatrician. Send questions to Bridgeport Hospital Center for Geriatrics, 95 Armory Road, Stratford CT 06614 or geriatricmd@aol.com.

A drug for Down syndrome

from the New York Times:

Early in the evening of June 25, 1995, hours after the birth of his first and only child, the course of Dr. Alberto Costa’s life and work took an abrupt turn. Still recovering from a traumatic delivery that required an emergency Caesarean section, Costa’s wife, Daisy, lay in bed, groggy from sedation. Into their dimly lighted room at Methodist Hospital in Houston walked the clinical geneticist. He took Costa aside to deliver some unfortunate news. The baby girl, he said, appeared to have Down syndrome, the most common genetic cause of cognitive disabilities, or what used to be called “mental retardation.”

 

Photograph from Alberto Costa

Tyche in kindergarten when she was 5, learning how to write her name.

Costa, himself a physician and neuroscientist, had only a basic knowledge of Down syndrome. Yet there in the hospital room, he debated the diagnosis with the geneticist. The baby’s heart did not have any of the defects often associated with Down syndrome, he argued, and her head circumference was normal. She just didn’t look like a typical Down syndrome baby. And after all, it would take a couple weeks before a definitive examination would show whether she had been born with three copies of all or most of the genes on the 21st chromosome, instead of the usual two.

Costa had dreamed that a child of his might grow up to become a mathematician. He had even prevailed upon Daisy to name their daughter Tyche, after the Greek goddess of fortune or chance, and in honor of the Renaissance astronomer Tycho Brahe. Now he asked the geneticist what the chances were that Tyche (pronounced Tishy) really had Down syndrome.

“In my experience,” he said, “close to a hundred percent.”

Costa and his wife had been trying to have a baby for a couple of years. Daisy’s first pregnancy ended in a miscarriage, which they knew can occur because of a genetic disorder in the fetus. When Daisy became pregnant a second time, Costa insisted they get a chorionic villus sampling, an invasive prenatal genetic test. But the procedure caused a miscarriage. (The test showed that the fetus was genetically normal.) Costa vowed that if there was a third pregnancy — this one — they would conduct no prenatal tests.

Now, with Tyche bundled peacefully in a bassinet at the foot of Daisy’s bed, and Daisy asleep, Costa sat up through most of the night crying. He had gone into the research side of medicine in part to avoid scenes like this — parents devastated by a diagnosis. But by morning, he found himself doing what any father of a newborn might: hovering by the crib, holding his daughter’s hand and marveling at her beauty.

“From that day, we bonded immediately,” he told me during one of our many talks over the last year. “All I could think is, She’s my baby, she’s a lovely girl and what can I do to help her? Obviously I was a physician and a neuroscientist who studies the brain. Here was this new life in front of me and holding my finger and looking straight in my eyes. How could I not think in terms of helping that kid?”

With no experience in the study of Down syndrome, Costa took a short walk the next day to a library affiliated with Baylor College of Medicine, where he worked as a research associate in neuroscience.

Reading the latest studies, he learned that the prognosis was not nearly as dire as it was once considered.

Life expectancies had grown, education reforms had produced marked gains in functioning and — of particular interest to Costa — a mouse model of the disorder had recently been developed, opening the door to experimentation. He soon made a decision: he would devote himself to the study of Down syndrome.

In 2006, using mice with the equivalent of Down syndrome, Costa published one of the first studies ever to show that a drug could normalize the growth and survival of new brain cells in the hippocampus, a structure deep within the brain that is essential for memory and spatial navigation. In people with Down syndrome, the slower pace of neuron growth in the hippocampus is suspected to play a key role in cognitive deficits. Follow-up studies by other researchers reached conflicting results as to whether the drug Costa had tested, the antidepressant Prozac, could produce practical gains on learning tests to match its ability to boost brain-cell growth. Undeterred, Costa moved on to another treatment strategy. In 2007 he published a study that showed that giving mice with Down syndrome the Alzheimer’s drug memantine could improve their memory.

Now Costa has taken the next step: he is completing the first randomized clinical trial ever to take a drug that worked in mice with Down and apply it to humans with the disease, a milestone in the history of Down-syndrome research.

“This was a disorder for which it was believed there was no hope, no treatment, and people thought, Why waste your time?” says Craig C. Garner, a professor of psychiatry and behavioral sciences and co-director of the Center for Research and Treatment of Down Syndrome at Stanford University. “The last 10 years have seen a revolution in neuroscience, so that we now realize that the brain is amazingly plastic, very flexible, and systems can be repaired.”

But the effects of that revolution on Down research may yet be cut short. A competing set of scientists are on the cusp of achieving an entirely different kind of medical response to Down syndrome: rather than treat it, they promise to prevent it. They have developed noninvasive, prenatal blood tests which would allow for routine testing for Down syndrome in the first trimester of a pregnancy, raising the specter that many more parents would terminate an affected pregnancy. Some predict that one of the new tests could be available to the public within the year.

Costa, like others working on drug treatments, fears that the imminent approval of those tests might undercut support for treatment research, and even raises the possibility that children like Tyche will be among the last of a generation to be born with Down syndrome.

“It’s like we’re in a race against the people who are promoting those early screening methods,” Costa, who is 48, told me. “These tests are going to be quite accessible. At that point, one would expect a precipitous drop in the rate of birth of children with Down syndrome. If we’re not quick enough to offer alternatives, this field might collapse.”

So recently was the genetic cause of Down syndrome established that just this past March, Costa actually met the widow of the French scientist, Jérôme Lejeune, who made the discovery in 1959. The scene of their meeting was a Paris conference, named in honor of Lejeune, where neuroscientists from around the world discussed progress into treatments for Down and related diseases. Such a conference would have been inconceivable when Costa entered the field 15 years ago.

“If you think about most genetic diseases, they’re usually caused by one gene, and in fact one mutation at one amino acid,” says Roger Reeves, a professor at the Institute for Genetic Medicine at the Johns Hopkins University School of Medicine. “But with Down syndrome, you have an extra copy of all 500 or so genes on Chromosome 21.” In the first two decades after Lejeune’s discovery, the very idea of grappling with those hundreds of triplicated genes scared off scientists from any serious effort to find a treatment for what they were soon calling “trisomy 21.” It just seemed impossibly complex. “The turning point,” Reeves says, “came when Muriel Davisson made her mouse.”

Davisson, now semiretired from Jackson Laboratory in Bar Harbor, Me., spent the 1980s developing a mouse, known as Ts65Dn, that had many of the traits associated with Down syndrome, including, incredibly, the distinctive facial characteristics associated with the disease and the same slightly uncoordinated gait.

Five years after publishing news of her mouse, Davisson received an e-mail from a young neuroscientist named Alberto Costa. Her work, he told her, opened the door for him to conduct meaningful new drug research.

“It was an epiphany, that, oh, this is a field where I can apply a lot that I’ve learned,” Costa says. “Science is usually unforgiving with people who try to change career paths, but it was a risk I was willing to take.” Having earned his Ph.D. studying the electrical and chemical basis of communication between brain cells, “I figured, O.K., if there is something that can be done in this field, it’s going to be done at that level of neuronal electrophysiology.” After months of reading the latest studies, Costa knew he needed Davisson’s mice.

“He twisted my arm till I took him into my lab,” Davisson says with a laugh. “I didn’t have funding. He wrote a grant to get the funding. He is very enthusiastic.” She also found out that he was a “perfectionist, and not very tolerant of people who aren’t perfectionists. He doesn’t do experiments without being sure he’s doing them right. When he makes a finding, you know that it’s real.”

Using Davisson’s mice, Costa’s 2006 study with Prozac produced cellular changes in the brain. In 2007, Craig Garner at Stanford took the next step, reporting behavioral improvements in Ts65Dn mice after weeks of drug treatment. (Earlier this year, a company he co-founded to pursue that strategy received funding from a venture-capital firm.) Four months later, Costa published his memantine study, showing that a single injection of the drug produced behavioral benefits within minutes, enabling Down-equivalent mice to learn as well as standard mice.

Memantine works, Costa hypothesizes, not by boosting the growth of brain cells but by normalizing how existing cells use the neurotransmitter glutamate. Because people with Down syndrome have three copies of all or most of the genes on Chromosome 21 instead of just two, they have about 50 percent more of any proteins encoded in that chromosome. One result, Costa has shown, is that the NMDA receptors of Ts65Dn mice are “hyperactive” — they overreact to stimuli. By responding to too many things, they learn too little; the signal is lost amid the noise. But giving memantine to quiet the noisy NMDA receptors, Costa has found, makes the brain cells react almost normally.

Other drugs that work on different systems in the brain have also shown benefits in the Ts65Dn mouse. In 2009, Dr. William C. Mobley, chairman of neurosciences at the University of California, San Diego, and one of the most active and visible researchers in the field, co-wrote a study showing that a combination of drugs designed to raise norepinephrine levels in the brain normalized the mice’s learning abilities. Most recently, last year the Nobel laureate Paul Greengard of Rockefeller University showed that memory and learning could be normalized in Ts65Dn mice by lowering levels of beta amyloid, the protein goop that has long been known to clog the brains of people with Alzheimer’s disease.

“There’s been a sea change in our ability to understand and treat Down syndrome,” Mobley says.

“There’s just been an explosion of information. As recently as the year 2000, no drug company would possibly have thought about developing therapies for Down syndrome. I am now in contact with no less than four companies that are pursuing treatments.”

Costa’s current memantine study began by testing memory and spatial learning in 40 young adults with Down syndrome. Daily, for 16 weeks, half received memantine pills, the other half a placebo. This fall, Costa will present preliminary results at a scientific meeting in Illinois on whether taking the drug made those with Down, in a word, smarter.

A half-hour from his office and laboratory at the University of Colorado-Denver School of Medicine, where he is an associate professor of medicine and neuroscience, Costa pulled into a parking space in front of his modest two-bedroom apartment. The figure of a girl in green dashed toward the car — and then vanished.

“Tyche,” Costa called to his daughter, “where’d you go?”

We both stepped out to look for her. I found her standing in front of another car, a Subaru Forester, waiting to get in. Dressed in a lime-colored shirt and skirt, the bangs of her mahogany hair framed by a hair band, Tyche stood just 4 feet 6 inches tall, with a round face, broad nose and heavy-lidded eyes.
Seeing my puzzled look, Costa explained that they also owned the Subaru — which he usually drove with Tyche. He led her to the Toyota we’d arrived in, where she sat down in the back seat. As Costa drove us to his office, I asked what she thought of her father’s work.

“He’s the greatest scientist,” she said, in a slurred, high-pitched voice. Then she added with a laugh, “And he builds evil machines.”

“That’s from watching too many cartoons,” Costa said. “Her favorite is ‘Phineas and Ferb.’ Of course, there’s an evil scientist in it who builds all kinds of machines.”

“Like the Smell-inator,” added Tyche, who turned 16 in June.

Back at Costa’s office, Tyche demonstrated to me what people with Down can be capable of even without medication. (Because she’s not an adult, Tyche is ineligible to participate in her father’s study.)

On the whiteboard at the front of the room, Costa wrote out an algebra problem for her to solve: 8x² - 7 = 505.

“She’s one of only two people with Down syndrome who I’ve ever known to be capable of doing algebra,” Costa said. “Normally we give her a problem before she goes to bed.” As she solved the equation, taking six steps to conclude that X equals 8, he said, “It’s basically instead of a bedtime story.”

This past Christmas, he proudly noted, he gave her the Rosetta Stone language program for learning Portuguese, and by March she had finished with Level 1 and begun Level 2.

It turns out that with vigorous education and support, many people with Down do far better than once thought possible. Medical care of heart and other physical ailments associated with the disorder have likewise achieved significant benefits, doubling the average lifespan from 25 to 49, in just the 14 years between 1983 and 1997.

Still, with an I.Q. that is typically around 50 points lower than average — with some far lower and others, like Tyche, reaching higher — something more than education alone would be necessary to enable the majority of people with Down syndrome to live independently. Costa said he hopes that memantine might be that something, raising I.Q. noticeably, even if modestly. For him, the goal is to help people with Down syndrome achieve autonomy. “At some point, you want your children to have their own life,” he said. “It’s about independence.”

Costa was raised in Brazil, the son of a marine officer and a seamstress. When he was 14, his parents divorced. His father sent little support, and he and his two siblings lived with their mother in poverty. Perhaps inevitably for someone who had to struggle to rise above his circumstances, he comes across as intense and consumed by his work; he hasn’t taken a vacation since Tyche was 3. But he is also devoted to his daughter and wife, spending most of every weekend with them.

“She’s a great kid,” he said. “She has a very strong personality. In many ways she has features of a regular teenager. She doesn’t like me to get into her bedroom. She loves pop music and vampires.” Her relatively high functioning, he told me, is important to him. “If Tyche were really severely affected, I don’t know if I would have had the energy to go on with this business.” Then again, he admits to having paternal feelings toward all 40 young adults in his study, whose cognitive abilities vary widely. “At the end of the day,” he said, “their parents know someone really cares for their kid. It’s not an academic experience for me. It’s my life.”

In January, and again in March, a spate of news reports described new studies of the noninvasive blood tests that would allow pregnant women to check for Down syndrome without the risks and discomfort associated with chorionic villus sampling and amniocentesis. Few of the articles, however, took note of the profound unease many medical ethicists, including some who are ardently pro-choice, feel about the tests and how they might lead to a dramatic reduction in the Down syndrome population.

“Even people who are traditionally against abortion are sometimes willing to condone it when the abortion is of a fetus with a disabling trait,” says Erik Parens, a bioethicist at the Hastings Center in Garrison, N.Y. “But it’s important to recognize that there is a huge range of genetic disorders. In their own way, a lot of kids with Down syndrome flourish, and so do their families.”

Advocates of the new tests insist that parents will be given news of an affected pregnancy by a trained geneticist who will present the information fairly and fully. Critics, including Costa and many other parents of children with Down syndrome, say that such dispassionate approaches rarely happen in practice, with many obstetricians and genetic counselors providing unduly negative or misleading information.

But Stephen Quake, a professor of bioengineering and applied physics at Stanford and a developer of one of the new tests, says: “It’s a gross oversimplification to assume that these tests are going to lead to the wholesale elimination of Down-syndrome births. My wife’s cousin has Down syndrome. We just celebrated his 21st birthday. He’s a wonderful person. It’s not an obvious step that you would terminate an affected pregnancy.”

But Costa points to a falloff in the financing of Down-syndrome research since the prenatal tests have been in development. Although it’s difficult to compare the numbers, money from the National Institutes of Health dropped to $16 million in 2007 from $23 million in 2003, before creeping back up to $22 million in 2011. That’s far less than the $68 million slated for cystic fibrosis, which affects an estimated 30,000 people in the United States, at most one-tenth of the 300,000 to 400,000 people who have Down.

“The geneticists expect Down syndrome to disappear,” Costa says, “so why fund treatments?”

Alan Guttmacher, director of the National Institute of Child Health and Human Development, denies that this is the calculus used by his organization. Yet he offered no clear answer when I asked him why about $3,000 in research dollars is spent by N.I.H. for every person with cystic fibrosis, compared with less than $100 for every person with Down.

“The number affected is a fair metric to use,” Guttmacher said. But, he pointed out, most of N.I.H.’s funding decisions are based on the strength of proposals coming from researchers. Advocacy groups for disorders like AIDS, autism and breast cancer have certainly played a role in their gaining increased funding, he said. And perhaps, he speculated, Down suffers from an image problem. “Part of it is that Down syndrome has been around for so long,” he said.

Representative Cathy McMorris-Rodgers, Republican of Washington, who co-founded the Congressional Down Syndrome Caucus soon after her 4-year-old son, Cole, was born with the disorder, has had little success in having money appropriated for Down research.

“I find myself wondering how N.I.H. really sets their priorities,” she told me. “I’m quite concerned that so many of the researchers in the Down-syndrome field have difficulty getting funded.” She continued, “My fear is that for some, they believe that it’s been taken care of through prenatal diagnosis.”

Even Costa has struggled to secure financing. He lives with Tyche and Daisy in a rented apartment, having never felt he had enough job security to buy a home. At his laboratory, some of his most expensive and sophisticated equipment for studying Down syndrome remains in storage, literally gathering dust for want of financing to use it. One source of his research money has been the Anna and John J. Sie Foundation, based nearby in Denver, and run by Michelle Sie Whitten, whose 8-year-old daughter has Down syndrome. Three years ago, the foundation established a research institute at the University of Colorado in Denver, where Costa works.

Plainly, though, he didn’t get into Down-syndrome research for the money. “There’s a reason why I’m doing what I’m doing,” he told me, nodding toward Tyche.

Not all parents of children with Down syndrome embrace Costa’s vision of a medical treatment targeting intelligence. In a recent survey conducted in Canada, parents were asked what they would do if there was a “cure” for their child’s Down syndrome. A surprising 27 percent said they would definitely not use it, and another 32 percent said they were unsure.

Meanwhile, the major not-for-profit advocacy groups devoted to Down syndrome spend little on research, instead preferring to lobby and offer parental support. Fresh energy has come from two relatively new groups determined to turn the situation around — Research Down Syndrome and the Down Syndrome Research and Treatment Foundation — but even they have so far succeeded in each raising only about $1 million a year, a fraction of the annual research budgets of many other disease-­advocacy groups.
Behind the ambivalence toward treatments, some parents say, is a fear that increasing their children’s intelligence might change their personalities — their very identities.

“Nobody would be against giving insulin for diabetes,” said Michael Bérubé, director of the Institute for the Arts and Humanities at Pennsylvania State University and author of the 1996 book “Life as We Know It,” published five years after his second son, Jamie, was born with the disorder. “But Down syndrome isn’t diabetes or smallpox or cholera. It’s milder and more variable and more complicated. I’d be very leery of messing with the attributes Jamie has. He’s pretty fabulous. At the same time, I’m not doctrinaire. If you’re talking about a medication that allows people to function in society and hold jobs, how can you be against that?”

The parents I met whose children participated in Costa’s study expressed little of Bérubé’s ambivalence. Peggy Hinkle told me about changes she saw in her 26-year-old daughter. “When Christina was on the pills, she told me one morning about a dream she had. She gave me five full, complete sentences. Which is a very big deal. Not only that, she left the room and came back later and told me another sentence about the dream. And she started to do Jumble word puzzles in the newspaper. I don’t know if she was on the drug or on placebo, but after five weeks there was a change. Boom. That’s why we participated: to expand her horizons.”

For his part, Costa has no doubts about the work to which he has devoted the last 15 years of his life. “If you have a disorder that’s changing the function of an organ, which in this case is the brain, and you use a medication to bring the function of that organ closer to where it was meant to be from millions of years of evolution, that’s as fair as treating any other disease,” he said. “I don’t see it as any different.” If his current study is successful, Costa’s ultimate goal is to test it in youths, like Tyche, during the crucial early years of development. Costa is quick to point out that he has not offered her memantine outside the study, and he discourages other physicians from doing so until its safety and effectiveness is proved. But from his perspective as both a researcher and a father, he said: “The sooner you start, obviously, the greater would be your hopes. All I know is, the clock is ticking.”

Drug treatment for people with intellectual disabilities

From the Los Angeles Times:

Slouched sideways at his desk in the front row of class, a sneakered foot jittering distractedly, Chase Brown could be any 14-year-old in academic captivity.

As the discussion turns to the American history of slavery, the teacher draws Chase back from his apparent reverie. A classmate has said that Abraham Lincoln freed the slaves. Does Chase agree or disagree?

Chase locks eyes with his teacher. "I agree," he says emphatically.

It is a moment of triumph for Chase, one of an estimated 90,000 in the U.S. who live with an inherited form of intellectual disability known as fragile X syndrome. Only a year ago, he would have fled the classroom, thrown something at the teacher or stayed mute. Last year, he tested below first-grade level in all academic domains.

Impulsive, distracted and quick to boil over, he seemed incapable of learning.

This year, he can sit in a classroom for half an hour before needing a "sensory break": a walk around the parking lot to clear his overstimulated brain. He is reading at a fourth-grade level, following class discussions, looking teachers squarely in the eyes and answering questions.

On a surprising drug — a workhorse antibiotic used since the 1960s to treat acne, skin infections, strep throat and chlamydia — Chase is learning.

Minocycline, the medication Chase has been taking for almost eight months, is one of several drugs that might correct — even reverse — many of the brain perturbations of fragile X and several other developmental disorders, including autism.

The medications are still far from proven: Large-scale trials may take several years to complete. But if they live up to their promise without dangerous side effects, they could accomplish what no medication has been able to: cure a genetically based intellectual disability.

Last year, Chase was among the first 50 children and adults with fragile X to take the drug as an experimental treatment. Since then, said his mother, Heather Brown, he has changed in ways she hadn't thought possible.

He has developed the ability to chat: share details of his day, make thoughtful observations and inquiries, and respond with apparent understanding, even empathy.

His explosions of kicking, hitting and object hurling, and the terrible remorse that followed, have vanished.

It's not sedation: She saw that before when Chase cycled through a list of powerful antipsychotic medications. He seems instead to be learning new ways to behave.

"It's life-changing, it really is," said Brown, who lives in Mission Viejo with Chase and his stepfather. "I was, like, 'Minocycline? They use that for acne.'"

The condition that Chase was born with is caused by an abnormal elongation of a portion of DNA on the X chromosome. It is the most common inherited intellectual disability worldwide, affecting about 1 in 4,000 babies. It causes some cases of autism. Depending on the extent of the error, a child with fragile X can range from nonverbal to having communications skills that are mildly impaired. Epilepsy is common. Short-term memory deficits and very short attention spans can short-circuit academic progress.

It can seem like a train wreck of conditions — autism, attention deficit, bipolar disorder, anxiety and more — rolled into a single kid.

Yet now there's some genuine muscle pulling on the hope side of the equation, thanks to a confluence of parental activism, advances in brain science and luck.

"People haven't thought about what it would be like to reverse intellectual disability or mental retardation," says Dr. Randi Hagerman, medical director of UC Davis' MIND Institute, who ran the minocycline study in which Chase was enrolled. "We now think it may be possible."

It's a goal as controversial as it is ambitious. For decades, activists and parents championed inclusion for those with what was until recently called "mental retardation" (the preferred term now is "intellectual disability" or "developmental disability").

Somewhere along the way, many came to reject the idea that a "cure" was needed, or desirable. To suggest that intellectual disability is an illness crying out for a fix devalues and stigmatizes these children, they contended.

Advances in biomedical research have already begun putting that conviction to the test for families of those with Down syndrome.

In 2009, researchers at Stanford University School of Medicine and Packard Children's Hospital announced "a ray of hope" for those born with the condition. Working with mice bred to have the equivalent genetic error, they identified a faulty brain mechanism that disrupts the laying down of certain memories and, in turn, learning.

They also found that a readily available drug cocktail that boosts the brain chemical norepinephrine could compensate for the problem, enabling the mice to learn normally. With early use, the scientists suggested, such a drug might put a child born with Down syndrome on a normal cognitive trajectory.

Not all parents hailed this "ray of hope." Reacting to the news on a blog called Contrarian, Jenn Power, a Canadian mother of twin boys with Down syndrome, echoed the views of many who have been active in promoting the rights of those with intellectual disabilities.

"They do not need a needle in their brain to make them more functional, to help them find their car keys," she wrote. "What they need is a society that values what they have to offer."

After physicians recognized in Chase the classic profile of a fragile X child five years ago, he was treated with psychiatric medications, with limited results.

When puberty set in, his anxiety, aggression and repetitive behaviors escalated dramatically — along with his size and strength.

Heather Brown, a 38-year-old office manager for an electric contracting company, worried for his safety — and sometimes her own.

"I was dealing with hitting and kicking and throwing stuff," she said.

By then, she and her ex-husband, Chris, who lives in Carlsbad, had met UC Davis' Hagerman, who urged them to consider participation in her minocycline study. It went on to show that 70% of those with fragile X responded with significant improvement in language, behavior and cognitive function.

Minocycline's effectiveness in these early trials appears to be due to its suppression of a protein called MMP-9, which is overproduced in fragile X brains, derailing normal neural development. The antibiotic also tamps down inflammation in the brain. Both effects, amazingly, are incidental to the drug's antibiotic powers.

The drug's principal side effect in the studies is a graying of the teeth. A small number of patients developed blood signs suggestive of autoimmune inflammation, albeit with no associated symptoms.

Beyond minocycline, early trials are underway for three medications that inhibit a second protein that is overactive in fragile X brains and for a fourth drug, arbaclofen, that acts on yet another brain chemical. Arbaclofen appears from early drug-trial results to reduce the hyperactivity and hypersensitivity that are hallmarks of fragile X, and may help children with autism unrelated to fragile X.

Mark Bear, a neuroscientist at MIT's Picower Institute, says there's universal agreement that such drugs should produce the most dramatic changes in young children. But conducting early trials on very young children raises ethical and safety concerns, so they will focus on adults with fragile X for now.

Though this may limit the findings, "we have our fingers crossed that we'll still see substantial benefit," Bear said.

Many of the drugs considered promising for fragile X also have excited interest as treatments for a wider range of neurological conditions — stroke, spinal cord injury, multiple sclerosis, autism and Alzheimer's disease — a fact that will probably speed their path to market.

Chase, in the meantime, will continue to take minocycline, now prescribed off-label by Hagerman because the trial in which he participated is over.

"I'm sure people thought he might be a lost cause," his mother said of his situation before his treatment began. "I did wonder myself."

She said she didn't know what to make of today's talk of potential "cures." But now she sees a future in which her son might navigate the adult world — complete high school, have a job, an apartment, a girlfriend — with just a little help from family and social services.

"I'm definitely thinking differently," she said. "He's on a good path."