Drugs that boost the chemical messenger norepinephrine in the brain have been shown to alleviate cognitive problems in mice engineered to mirror Down syndrome. The findings, published today in the journal Science Translational Medicine, suggest a new approach to treating the disorder. Several existing drugs can boost the chemical or mimic its effects, though none have yet been tested in patients with Down syndrome.
The research also reflects a growing understanding of the brain systems that underlie the cognitive problems in people with Down syndrome, and better methods of developing potential treatments.
Down syndrome, which affects 5,000 infants in the United States each year, results from a duplication of a segment of chromosome 21. People with the disorder have lower than normal cognitive abilities and almost all develop signs of Alzheimer’s disease by middle age. Although no treatments for the cognitive deficits of Down syndrome exist currently, recent research in animal models of the disorder has unearthed a handful of candidates.
“This is one of several potential approaches identified in the last couple of years that suggest that small molecules, or even approved drugs, can be used to have a positive impact on cognitive function in Down syndrome,” says Roger Reeves, a scientist at the Johns Hopkins University School of Medicine in Baltimore, who was not involved in the new study.
At the heart of this research is a strain of mice with a duplication of a segment of chromosome 16 that mimics the genetics of the human disorder–the region contains more than 100 genes analogous to those affected by the duplication of human chromosome 21, and the animals show some of the same brain abnormalities. For example, the mice have major deficits in the hippocampus, a brain area vital for learning and memory. These facets are also impaired in humans with Down syndrome.
The new findings help identify neurological impairments caused by Down syndrome, and show that drug treatments can help alleviate the effects of these impairments. According to the research, the animals have signs of serious degeneration in a part of the brain called the locus coeruleus, which supplies the chemical messenger norepinephrine to the hippocampus. Norepinephrine is believed to help the hippocampus integrate different information, such as navigational and sensory input, says Ahmad Salehi, a scientist at Stanford and lead author on the paper.
The modified mice have problems with memory tasks that require this type of integration. For instance, the researchers taught both normal and engineered mice to fear a particular tone by pairing it with an electrical shock. Both mice froze when they heard the tone but normal mice also froze when placed in the box that they learned to associate with the tone and the shock, a phenomenon called contextual learning. Mutant mice failed this test, and children with Down syndrome have a similar deficit, says Salehi. “If you ask a kid [with Down syndrome] to enter a room from one door and find a toy, based on a cue like color, they can find it,” he says. “But if you change the door they enter, and don’t give them a cue, it takes them much longer to find the toy.”
Salehi and collaborators found that these problems could be reversed in mice by giving them a drug, l-threo-dihydroxyphenylserine (l-DOPS), which is converted into norepinephrine in the brain. Within a matter of hours, “there was no difference [in performance] between normal and [genetically engineered] mice after the treatment,” says Salehi. The effects wore off as norepinephrine levels declined.
A second drug, xamoterol, which activates a specific subset of norepinephrine receptors, had the same effect. However, xamoterol has undesirable side effects–it is a cardiac stimulant currently used to treat heart failure, making it an unlikely candidate for a Down syndrome drug.
L-DOPS was originally developed in Japan as a potential therapy for Parkinson’s disease. It is already sold in Asia for treatment of orthostatic hypotension and is currently being tested in clinical trials in the United States for orthostatic hypotension, fibromyalgia, and attention-deficit hyperactivity disorder (ADHD). Drugs that boost norepinephrine activity by blocking its re-uptake are also available, including atomoxetine (Strattera), which is approved for treatment of ADHD. Salehi now plans to test that drug in mice.
Norepinephrine drugs aren’t the first to show promise for treating the cognitive problems of Down syndrome. For example, memantine, a drug currently used to treat Alzheimer’s disease, also improves cognitive function in animal models of Down syndrome. A clinical trial of the drug in people with the disorder is currently underway. Small studies of a second Alzheimer’s drug, donepezil (Aricept), have shown mixed results in people with Down syndrome.
“Down syndrome is a very complex genetic disorder,” says Frances Wiseman, a scientist at University College London who wrote a commentary accompanying the article. “Therefore it’s likely that a combination of therapies will be needed to treat different aspects of learning and memory.”
Experts say that conducting large clinical trials of these drugs will be a challenge–scientists must develop reliable ways to measure improvement in the types of learning and memory that are most affected in the disorder, and then recruit enough people from the relatively small Down syndrome population to provide the statistical power to detect an improvement. Salehi cautions parents against trying these drugs before they have been tested in large, placebo-controlled clinical trials. “Just because a drug works in mice doesn’t guarantee the same effects in humans,” he says.
Researchers attribute recent advances to a growing understanding of the mechanisms underlying the disorder. “The ability to study the neurophysiology in the animal brain at least is becoming much more sophisticated,” says Charles Epstein, a physician and scientist at the University of California, San Francisco. Epstein says there have been big improvements in researchers’ ability “to look at specific systems and how they function and what might be beneficial in those systems.”
The new findings may also be relevant to Alzheimer’s disease. Patients with Alzheimer’s also show damage in the locus coeruleus, and virtually everyone with Down syndrome develops the plaques and tangles in the brain that characterize Alzheimer’s. To date, few people have studied the effects of drugs such as l-DOPS on Alzheimer’s patients, says Paul Aisen, a physician and scientist at the University of California, San Diego, director of the Alzheimer’s Disease Cooperative Study, and one of the authors on the current study. “This study suggests that we need to explore this strategy further.”
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