Poor Sleep as a Precursor to Cognitive Decline in Down Syndrome : A Hypothesis

On World Down Syndrome Day I want to highlight a well-known and natural treatment for cognitive / behavioral problems. - JR

Poor Sleep as a Precursor to Cognitive Decline in Down Syndrome : A Hypothesis.

Fernandez F1, Edgin JO2.

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• 1Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
• 2Department of Psychology and Cognitive Science Program, Sonoran University, Center for Excellence in Developmental Disabilities, University of Arizona, Tucson, AZ 85721, USA.

Fabian Fernandez1,* and Jamie O Edgin2

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Abstract

We propose that sleep disruption is a lever arm that influences how cognition emerges in development and then declines in response to Alzheimer disease in people with Down syndrome. Addressing sleep disruptions might be an overlooked way to improve cognitive outcomes in this population. This article is a contribution to a Special Issue on Down Syndrome curated by the editors of the Journal of Alzheimer’s Disease & Parkinsonism.

Keywords: Down syndrome, Alzheimer’s disease, Sleep disruption, Circadian arrhythmia

Trisomy for human chromosome 21 (Hsa21; Down syndrome, DS) results in a unique trajectory of developmental outcomes for the brain and craniofacial skeleton. In those with DS, the brain’s overall complexity is reduced owing to fewer cells and narrowing within the sulci and gyri that form its outer contour [1, 2]. Local and interregional connectivity may be altered due to weaker insulation of long-range projections by myelin [3–6], and to differences in how synapses and dendrites mature in response to behavioral experience [7, 8]. Infants with DS exhibit smaller neurocraniums at birth and altogether different morphometric relationships between individual bones of the craniofacial skeleton [9]. These divergent craniofacial features impact breathing [10]. Specifically, tissue crowding produced by midface hypoplasia and realigned soft tissue (i.e., constriction of the pharynx and palate, posterior displacement of the tongue, enlarged tonsilsadenoids) curtails airflow through the upper respiratory tract [11–17]. Propensity toward obesity and reduced muscle tone put further strains on the upper airways [18]. As a result of these medical issues, virtually all people with DS will present symptoms associated with obstructive sleep apnea syndrome (OSAS) and sleep fragmentation [18–24]. The loss of sleep quality wrought by OSAS is predicted to contribute to at least some of the everyday intellectual difficulties experienced by people with DS, presenting a case study in how developmental pathways affected by an extra copy of Hsa21 interact at a macro-level to influence cognitive outcomes later in life.

In this review, we discuss recent evidence linking sleep disruption to Alzheimer disease (AD) and cognitive decline in the typical non-DS population, and stipulate that DS is a population in which these elements might converge. Given the high prevalence of OSAS and AD in DS, we propose that sleep disruption could predispose individuals with DS to earlier onset or faster deterioration with dementia. These factors may be inextricably connected to the DS phenotype-to the extent that all future studies on cognitive development from infancy or cognitive decline in DS must take problematic sleep into account.

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Webinar - Sleep & Down Syndrome from Down Syndrome Research Center at Stanford Univeristy

JOIN US FOR OUR JANUARY WEBINAR

Dr. H. Craig Heller, Stanford University Tuesday, January 29, 10 AM PT / 1 PM ET What can we learn about Down syndrome by studying the neural mechanisms of sleep? Plenty, according to H. Craig Heller, Ph.D., co-director of Stanford's Down Syndrome Research Center.  Dr. Heller, an expert in the area of sleep and a DSRTF grant recipient, joins us for our January webinar to discuss the roles that sleep and circadian rhythm may play in the cognitive impairment that occurs in people with DS. Register now for this free one-hour presentation, then join us on Tuesday, January 29 at 10 AM PT / 1 PM ET to learn what research tells us about the influence of sleep and circadian rhythm on learning, memory, and attention — and what that may suggest for the future of improved cognition. We look forward to seeing you there. The DSRTF Team

Drug Shown to Improve Memory in Those With Down Syndrome

ScienceDaily (July 17, 2012) — esearchers at the University of Colorado School of Medicine have found a drug that boosts memory function in those with Down syndrome, a major milestone in the treatment of this genetic disorder that could significantly improve quality of life.

"Before now there had never been any positive results in attempts to improve cognitive abilities in persons with Down syndrome through medication," said Alberto Costa, MD, Ph.D., who led the four- year study at the CU School of Medicine. "This is the first time we have been able to move the needle at all and that means improvement is possible."

The study was published July 17 in the journal Translational Psychiatry.


Costa, an associate professor of medicine, and his colleagues studied 38 adolescents and young adults with Down syndrome. Half took the drug memantine, used to treat Alzheimer's disease, and the others took a placebo.

Costa's research team hypothesized that memantine, which improved memory in mice with Down syndrome, could increase test scores of young adults with the disorder in the area of spatial and episodic memory, functions associated with the hippocampus region of the brain.

Participants underwent a 16-week course of either memantine or a placebo while scientists compared the adaptive and cognitive function of the two groups.

While they found no major difference between the groups in adaptive and most measures of cognitive ability, researchers discovered that those taking memantine showed significant improvement in verbal episodic memory. One of the lowest functioning individuals in the study saw a ten-fold increase in memory skills.

"People who took the medicine and memorized long lists of words did significantly better than those who took the placebo," said Costa, a neuroscientist specializing in Down syndrome research. "This is a first step in a longer quest to see how we can improve the quality of life for those with Down syndrome."

Currently, there are drugs that treat the symptoms of medical conditions associated with Down syndrome but nothing to improve brain function.

But in 2007 Costa demonstrated that memantine could improve memory in mice with Down syndrome. He then set out to replicate those findings in a human trial of the drug.
"This is an excellent example of translational science," he said. "We took a drug that worked well in mice and we tested it in humans with positive results."

Although the trial was small, the results could have far-reaching implications. Costa said a follow-up study was needed using a larger group of people with Down syndrome. Another important step will be to pursue studies with younger, school-age participants with Down syndrome. They would have more rapidly developing brains and, since they are in school, would be routinely tested so the effects of the drug could be closely monitored. That could take as little as five years.

Researchers also want to know if memantine can ward off the onset of Alzheimer's disease in those with Down syndrome. The two conditions show striking similarities and researchers are actively exploring how they may be linked. Babies born with Down syndrome, for example, often carry the biological markers for Alzheimer's disease.

"Everyone with Down syndrome will develop Alzheimer's disease pathology by their mid-30s," Costa said. "We would like to know if this drug can slow down or even halt the development of that disease in adults with Down syndrome."

Memantine works by normalizing the function of a glutamate receptor in the brain known as the N-methyl-D-aspartate or the NMDA receptor.

"This receptor plays a central role in memory and learning," Costa said.
Given the small size of the study and the need for more research, Costa stressed that people should not start taking memantine for Down syndrome. Although it has proven safe and well-tolerated by the study participants, researchers urge caution, saying more work needs to be done to determine if this is a viable treatment option.

"Our study is a significant and hopeful sign that certain drugs can enhance the intellectual capacity of those with Down syndrome," he said. "For more than 30 years we have been unable to impact cognition in Down syndrome. Now it appears that we may be able to."

Costa has a major stake in improving the lives of those with Down syndrome, the most common cause of intellectual disability. He has a 17-year-old daughter with the condition.
"For me this research is not merely academic," he said. "It's personal."
The CU School of Medicine's work on Down syndrome has resulted in it being chosen as one of nine national testing centers for a new drug manufactured by F. Hoffmann-La Roche LTD aimed at improving memory in adults with Down syndrome. Costa is the principal investigator of the Colorado center.

He will give a lecture about his latest research July 20 in Washington D.C. at the 2012 Annual Meeting & Clinical Symposium of the Down Syndrome Medical Interest Group -- USA. The conference is being held from 1 p.m. to 9 p.m. at the Marriott Wardman Park, 2660 Woodley Rd. NW.

The other researchers in the study included Richard Boada, Ph.D., Christa Hutaff-Lee, Ph.D., David Weitzenkamp, Ph.D., Timothy A. Benke, MD, Ph.D. and Edward J. Goldson, MD.
The trial was funded by Forest Research Institute Investigator Initiated Grant NAM-58. During the course of this study, Costa was also supported in part by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
"I also am grateful to the Anna and John J. Sie Foundation, the Linda Crnic Institute and the Coleman Institute for Cognitive Disabilities for believing in my research all these years. This work would not have been possible without their support in these harsh economic times," Costa said.

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