Children born with Down’s syndrome can receive excellent healthcare at specialized clinics, but once they become adults, their care often falls to doctors who may be less qualified to deal with their specific needs. The new Down Syndrome Center for Research and Treatment (DSCRT) aims to break that pattern by providing continuous healthcare to Down’s patients of all ages. Led by William Mobley, who took over the Department of Neuroscience at the University of California, San Diego, from the late Leon Thal, the new center plans to integrate treatment and therapy with academic research. Since people with Down’s are at high risk for Alzheimer’s disease, the center will make the nexus between the two disorders a prime research focus. Where can Down’s syndrome researchers make headway, and how can their work advance the AD field?
In this Webinar, held 1 June 2011, William Mobley shared his vision for the new center and discussed how the latest research sharpens researchers’ understanding of both diseases. Joining him for a panel discussion were Jorge Busciglio, University of California, Irvine; Ira Lott, also from UCI; DSCRT clinical director Michael Rafii; Ahmad Salehi, Stanford University, California; and Nicole Schupf, Columbia University, New York.
Listen to the Webinar
Individual presentations start at the following times in the recording:
Bill Mobley, 0:5:39
Nicole Schupf, 0:35:30
Ira Lott, 0:47:25
Jorge Busciglio, 1:01:00
Ahmad Salehi, 1:11:30
Michael Rafii, 1:23:32
William Mobley's Presentation
Nicole Schupf's Presentation
Ira Lott's Presentation
Jorge Busciglio's Presentation
Ahmad Salehi's Presentation
By Tom Fagan
Down’s syndrome is a developmental disorder caused by the presence of an extra copy of some, or all, of chromosome 21. The severity of symptoms depends on the extent of the chromosomal excess, but people with Down’s syndrome typically have distinctive facial features, are short, and have muscle and organ problems including heart disease. Their cognition typically is impaired compared to people of the same age. Though many genes on chromosome 21 influence biology in people with Down’s (see Korbel et al., 2009), the presence of an extra copy of the gene for amyloid precursor protein (APP) particularly interests AD researchers. People with Down’s produce more amyloid-β peptide in their brains than normal and, in time, they all develop Alzheimer’s pathology. Measuring cognition in people with Down’s is possible, and many of them show deteriorating cognitive skills with age. As modern medicine has increased the life expectancy of people with Down’s, it also has presented the additional challenge of preventing their cognitive decline.
In answering this call, researchers may also help people with sporadic Alzheimer’s disease. The two diseases have much in common. AD can be caused by an extra copy of the APP gene, for example (see Rovelet-Lecrux et al., 2006), and like AD, deposition of Aβ in the brain is an early sign of impending dementia in people with Down’s (see Lemere et al., 1996). Indeed, there is a major push to find the earliest pathological events in AD, and brain uptake of amyloid ligands, including Pittsburgh Compound B (PIB), suggests later cognitive decline in normal individuals (see ARF related news story). Just this spring, a small study showed PIB uptake in people with Down’s syndrome as young as 45, in brain regions that typically exhibit amyloid pathology (see Landt et al., 2011). Small clinical trials suggest that cholinesterase inhibitors, which temporarily compensate for cognitive decline in AD patients, can help people with Down’s syndrome as well (Kondoh et al., 2011), and this is supported by studies in mouse models of DS (Chang and Gold, 2008; Lockrow et al., 2011). Beyond that, should any of the experimental therapies currently in the pipeline for AD be offered to people with Down’s in formal trials as well?
After all, the 400,000 people in the U.S. with Down’s syndrome represent nearly 10 percent of the AD population. Because they are at such a high risk for dementia, are known to medicine before AD hits, and almost universally have amyloid pathology, people with Down’s present a unique opportunity to find treatments that can slow or even prevent Alzheimer’s. At the same time, they are also a vulnerable population. The cognitive impairment that can go along with Down’s has traditionally raised the bar on informed consent and related issues of protection of study participants on the part of physicians and institutional review boards, holding back research in the past.
Led by Bill Mobley, the new Down Syndrome Center for Research and Treatment (DSCRT) at the University of California, San Diego, aims not only to provide exceptional clinical care for patients with Down’s, but also integrate that care with research. Mobley hopes the center will play a major role in banking patient samples and histories to facilitate scientific endeavor, including clinical trials. Because it will understand the unique medical history of this well-defined group of patients, Mobley thinks center staff are poised to recruit patients into clinical trials more effectively and more quickly than usual. The center’s clinical director is Michael Rafii, who has experience treating people with both conditions. Rafii recently led the Phase 2 clinical trial of huperazine A for mild to moderate AD (see Rafii et al., 2011). In linking patient care with clinical trials for Down’s, the center echoes the mission that the Lou Ruvo Center for Brain Health, Las Vegas, Nevada, pursues for frontotemporal dementias and other neurodegenerative brain diseases (see ARF related news story). “The challenge is to continue to support the science at the level that allows us to come forward with ideas for trials,” said Mobley.
For Down’s, Mobley hopes that several trials will start soon. For example, there is strong evidence that inhibitory networks are overly dampened in Down’s syndrome. To address this, Roche has begun Phase 1 testing of RG1662; this is an inverse agonist of the GABAA receptor, a major inhibitory gateway in neuronal circuitry. Mobley intends the new Down Syndrome Center for Research and Therapy will be part of these trials. Evidence suggests that some GABAergic neurons might be hyperactive in AD as well (see Rissman and Mobley, 2011). Mobley believes a GABAB receptor antagonist would also be useful because cognitive problems in Down’s can be traced to excessive electrical inhibition. The GABAB receptor is coupled to the G protein-activated inward rectifying potassium type 2 channel (GIRK2), which, like APP, is encoded on chromosome 21 (see GIRK2 on AlzGene). GIRK2 is hyperactive in Down’s, making the channel yet another potential therapeutic target, possibly for both diseases.
Much insight into Down’s has come from using mouse models that mimic the extra dose of chromosome 21 (chromosome 16 in mice). Together with Mobley, who came to UCSD from Stanford, Ahmad Salehi found that mice with an extra copy of a chromosome 16 fragment lose noradrenergic neurons in the locus ceruleus (Salehi et al., 2009), and that simply giving those mice a noradrenaline agonist could reverse cognitive decline. Noradrenergic locus ceruleus damage is an early event in AD and a subject of renewed interest (see related ARF Webinar; see Braak and del Tredici, 2011). Since noradrenaline reuptake inhibitors are already approved for other conditions, those drugs could be fast-tracked toward study in Down’s syndrome, and potentially Alzheimer’s.
Much basic research, as well, remains to be done on Down’s syndrome. UCI has a long-standing program in DS and AD. There, Ira Lott is conducting a study to investigate why some people with Down’s have one of the hallmarks of AD, i.e., amyloid pathology, but show no cognitive decline (e.g., Haier et al., 2008). In AD, it is well known that some people have rampant amyloid plaques but normal cognition. Many researchers believe that these people have sufficient cognitive reserve to temporarily remain asymptomatic, but all the same are on the path to dementia. Is the same true for Down’s? Lott is currently recruiting people with Down’s age 40 and above, who show no signs of dementia. He plans to scan them for structural and functional brain changes and will take fluid and tissue samples for biomarker analysis. The longitudinal study could help researchers figure out what specific physiological changes make people with Down’s susceptible to dementia and what biomarkers might signal their decline.
Jorge Busciglio takes a complementary approach to the same question. Using fetal and adult cells from people with Down’s, he drills down to the cellular and molecular underpinnings of the disease. Busciglio’s group identified mitochondrial dysfunction as a major contributing factor to several manifestations of the syndrome, including type 2 diabetes, cognitive dysfunction, and dementia (e.g., Helguera et al., 2005; Busciglio et al., 2007). Most recently, he reported that, in the cell culture dish, dysfunctional astrocytes, the housekeeping cells of the brain, may be responsible for abnormal neuronal morphology, particularly the loss of dendritic spines and synapses, that contribute to cognitive decline (see Garcia et al., 2010).
Nicole Schupf’s interest lies in epidemiology. Schupf has been working with kids and adults with Down’s for many years. She reported that decreasing plasma Aβ42 in Down’s patients may be a harbinger of dementia (Schupf et al., 2010). She found that the age of onset of menopause predicts age of onset of dementia in Down’s syndrome (Schupf et al., 2003), and that estrogen protects women with Down’s from cognitive decline. Schupf also investigates the role of genetic polymorphisms in Down’s syndrome. For example, certain variants in the gene for the α isoform of the estrogen receptor increase the risk for Alzheimer’s in people with Down’s (see Schupf et al., 2008), while certain variants in the SORL1 gene that has been linked to sporadic AD seem to protect people with DS (Lee et al., 2007).
How can Down’s research drive insight about Alzheimer’s and vice versa? What are the major questions and challenges? What sorts of clinical trials, disease models, human brain imaging, and epidemiological studies hold the answers?
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