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>.

Scientist tests promising drug on those with Down syndrome

from Health Canal:

A University of Colorado School of Medicine scientist is finishing a major clinical trial on a drug that could boost cognitive function in those with Down syndrome, significantly improving their quality of life and representing a potential milestone in research on this genetic disorder.

“We are hoping to enhance memory and learning in those with Down syndrome,” said Alberto Costa, MD, Ph.D., an associate professor of medicine and the neuroscientist leading the effort.

“We have been studying this drug for three years and are now ready to analyze the data on our trial. Our team at the University of Colorado and Children’s Hospital Colorado expects to have the results in the next two or three months.”

Costa, whose work was chronicled in last Sunday’s New York Times Magazine, (A Drug for Down Syndrome), is tested the drug memantine, currently used to relieve symptoms of Alzheimer’s disease, in 39 people with Down syndrome. About half received the drug and the others a placebo. In 2007, Costa demonstrated that memantine could improve memory function in mice with Down syndrome.

And now, for the first time, he is taking a drug effective in the treatment of learning and memory deficits in mice with Down syndrome and applying it to humans, a move described by the New York Times as “a milestone in the history of Down syndrome research.”

Costa is no disinterested researcher, his 16-year-old daughter Tyche – named for the Greek goddess of Fortune - has Down syndrome. Like others with the condition, she faces the specter of a steady decline in mental functioning as she gets older and a roughly 20 percent chance of getting Alzheimer’s in her 50’s. After that diagnosis, death is often just five years away.

“I feel I am racing the clock to find something that will at least keep her functioning at the level she is at now,” Costa said. “As they age, parts of their brain will shrink and their functions will diminish.”

Costa is actively pursuing links between Down and Alzheimer’s disease. He says babies born with Down often carry the biological markers for Alzheimer’s.

“They have the disease from the get go,” he said.

Costa says the world is awash in false assumptions about Down syndrome ranging from distortions on life expectancy to educational limitations. In fact, depending on the severity of their condition, those with Down can live into their 70s, attend college, live independently and hold down jobs.

 

“If we are successful, it will increase hope and expectations for those with Down syndrome,” Costa said. “Right now there are drugs for the signs and symptoms of medical conditions more frequent in those with Down syndrome, but nothing to improve brain function. In fact, the prevailing wisdom has been that there is essentially nothing you can do to boost memory and learning in this group. Hopefully, we can prove them wrong.”

But he and other Down researchers face an overall lack of federal funding, especially when compared to other diseases and disorders.

Costa has been supported by Forest Pharmaceuticals which is funding the clinical trial, the Linda Crnic Institute for Down Syndrome, the Coleman Institute for Cognitive Disabilities at the University of Colorado and the National Institute of Child Health and Development, part of the National Institutes of Health.

“Clearly these funding sources are the unsung heroes,” Costa said. “They may not get the attention or publicity but I can assure you that our efforts and the future of those with Down syndrome would be seriously compromised without their continued generosity.”

Drug may reverse Down syndrome symptoms

from mother nature network:

 

Dr. Alberto Costa has a personal stake in his Down syndrome research: his daughter, Tyche.

 

Costa's life and work changed direction after she was born 16 years ago and Costa — a physician and neuroscientist — decided to dedicate his career to the study of Down syndrome.In the past decade and a half, Costa's research has focused on normalizing the brain cells in the hippocampus, the portion of the brain responsible for memory and spatial navigation.

 

In 2006, Costa published a study that found that a drug — the antidepressant Prozac — could normalize the cells in this area of the brain. But it was still unclear whether or not these normalized cells would automatically translate to better memory and improve cognitive deficits.

 

The next year, Costa worked with Down syndrome mice and found that the Alzheimer’s drug memantine could improve their memory. Costa's study showed that a single injection of memantine produced benefits within minutes, enabling Down-equivalent mice to learn as well as standard mice.

 

Costa's theory is that memantine works not by increasing or changing brain cells, but by normalizing how they work. People with Down syndrome have three copies of all or most of the genes on Chromosome 21 instead of just two, so receptors in this area of the brain tend to be hyperactive — overreacting to stimuli and making it difficult for the brain to focus and learn.

 

Memantine, according to Costa's hypothesis, quiets the noise, allowing the brain cells to react normally. Costa's journey was the focus of a feature story in this Sunday's New York Times Magazine.

 

Now Costa is working on the first randomized clinical trial to use the drug in humans. For Costa's trail, he is testing memory and spatial learning in 40 young adults with Down syndrome who have received memantine pills daily for 16 weeks. Costa will present preliminary results of this research at a scientific meeting in Illinois this fall. If successful, memantine could provide a new future for Costa's daughter Tyche and the 400,000 other people living with Down syndrome in the U.S.

Diagnosing Dementia In Adults With Down Syndrome

from ivanhoe.com:

A unique brain scanner is used to allow the assessment of amyloid plaques and neurofibrillary tangles- the hallmarks of Alzheimer's disease- in adults with Down syndrome. This finding may offer a new clinical tool to help diagnose dementia in adults with Down syndrome.

Adults with this disorder develop Alzheimer's-like plaque and tangle deposits early, often before the age of 40. Previously, the only way to physically detect these abnormal proteins in this population was through an autopsy.

Over the last decade, methods for identifying and imaging the neuropathology of Alzheimer's disease in living patients have been developed. UCLA researchers have created a chemical marker called FDDNP that binds to both plaque and tangle deposits, which can then be viewed through a positron emission tomography (PET) brain scan, providing a "window into the brain." Using this method, researchers are able to pinpoint where in the brain these abnormal protein deposits are accumulating.

"Early detection can also lead to earlier interventions and treatments, often before symptoms begin."
For this study, researchers intravenously administered FDDNP and then performed PET brain scans on 19 non-demented adults with Down syndrome (average age 37), 10 healthy controls (average age 43) and 10 patients with Alzheimer's disease (average age 66).

The results showed significantly higher binding levels of FDDNP in participants with Down syndrome in all brain regions, when compared to healthy controls. Compared with Alzheimer's disease patients, subjects with Down syndrome showed significantly higher binding levels in the parietal and frontal regions — areas involved in memory, behavior and reasoning.

"The higher level of plaques and tangles may be reflecting the early and extensive accumulation of these deposits seen in individuals with Down syndrome," Dr. Small said.

The researchers also discovered significant associations between increased age in those with Down syndrome and higher FDDNP binding values in the parietal, lateral temporal and frontal regions.

"This is one of the first times we've been able to visualize the neuropathology occurring in the living brains of adults with Down syndrome," study author Dr. Jorge R. Barrio, a professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA who holds UCLA's Plott Chair in Gerontology, was quoted as saying.

"The age-related patterns and regional distribution of the plaques and tangles were consistent with the types of deposits that could only be identified previously through an autopsy."
The areas of accumulation were consistent with earlier autopsy study findings, which had shown that while plaque and tangle pathologies are the same in both Down syndrome and Alzheimer's disease, the deposit patterns are different.

Autopsy studies have also shown that all adults with Down syndrome eventually develop these accumulations of amyloid plaques and tau tangles. But rather than experiencing memory decline and other cognitive losses, as is common with Alzheimer's, aging Down syndrome patients tend to develop behavioral problems.

"We found that the behavioral changes in the subjects with Down syndrome correlated with neurological changes in related areas of the brain consistent with the level of FDDNP binding levels to the abnormal proteins," Dr. Small said.