Genetic mutations may cause more cases of amyotrophic lateral sclerosis (ALS) than scientists previously had realized, according to researchers atWashington University School of Medicine in St. Louis and Cedars-Sinai Medical Center in Los Angeles. The scientists also showed that the number of mutated genes influences the age when the fatal paralyzing disorder first appears.
Washington University graduate student Janet Cady and assistant professor of neurology Matthew Harms, MD, found evidence that genetic mutations may contribute to more cases of amyotrophic lateral sclerosis (ALS) than scientists had realized. The illness destroys nerve cells that control muscles, eventually leading to paralysis and death.
ALS, also known as Lou Gehrig’s disease, destroys the nerve cells that control muscles, leading to loss of mobility, difficulty breathing and swallowing, and eventually paralysis and death. Understanding the many ways genes contribute to ALS helps scientists seek new treatments.
The study appears online in Annals of Neurology.
Scientists have linked mutations in more than 30 genes to ALS. Alone or in combination, mutations in any of these genes can cause the disease in family members who inherit them.
Roughly 90 percent of patients with ALS have no family history of the disease, and their condition is referred to as sporadic ALS. Scientists had thought mutations contributed to barely more than one in every 10 cases of sporadic ALS.
But researchers recently started to suspect that patients with sporadic ALS carry mutations in the 30 genes linked to ALS more often than previously thought. The new study is among the first to prove this suspicion correct.
“To our surprise, we found that 26 percent of sporadic ALS patients had potential mutations in one of the known ALS genes we analyzed,” said co-senior author Matthew Harms, MD, assistant professor of neurology at Washington University. “This suggests that mutations may be contributing to significantly more ALS cases.”
The scientists used a sequencing technique devised at Washington University to look at 17 known ALS genes in the DNA of 391 patients with ALS. Like the overall ALS patient population, 90 percent of the patients had no family history of disease.
It’s not yet clear why some patients with sporadic ALS have mutations linked to the illness but no family history of the disorder. Researchers don’t know if these patients are the first in their families to develop these mutations, or if these altered genes are present in other family members but do not cause the disorder. Harms noted that some of the mutations they identified might not contribute to disease at all.
“It’s also possible that these mutations could be combining with environmental factors linked to ALS,” said co-senior author Robert Baloh, MD, PhD, associate professor of neurology at Cedars-Sinai Medical Center. “Those factors might coincide in an individual family member and cause disease, while other family members who have the mutation but not the environmental exposures remain unaffected.”
The study also shows that having mutations in more than one ALS gene can accelerate the onset of symptoms. In patients with only one mutation, the average age of onset was 61, but in those with more than one mutation, the average age of onset was 51.
The scientists are analyzing genetic data from additional patients with ALS to confirm their findings.
The ALS Association estimates that 30,000 Americans have ALS at any given time. Riluzole, the sole medication approved to treat the disease, has only marginal benefits in patients.
This work was supported by the National Institutes of Health (NIH), grant numbers K08-NS075094 and R01-NS069669, and NIH Genetics Epidemiology Training Grant 5-T32-HL-83822-5.Cady J, Allred P, Bali T, Pestronk A, Goate A, Miller TM, Mitra R, Ravits J, Harms MB, Baloh RH. ALS onset is influenced by the burden of rare variants in known ALS genes. Annals of Neurology. Online Nov. 11, 2014.
A protein that stimulates the brain to awaken from sleep may be a target for preventing Alzheimer’s disease, a study by researchers at Washington University School of Medicine in St. Louis suggests.
In recent years, scientists at Washington University have established links between sleep problems and Alzheimer’s. For example, they have shown in people and in mice that sleep loss contributes to the growth of brain plaques characteristic of Alzheimer’s, and increases the risk of dementia.
The new research, in mice, demonstrates that eliminating the protein –called orexin – made mice sleep for longer periods of time and strongly slowed the production of brain plaques.
“This indicates we should be looking hard at orexin as a potential target for preventing Alzheimer’s disease,” said senior author David M. Holtzman, MD, head of the Department of Neurology. “Blocking orexin to increase sleep in patients with sleep abnormalities, or perhaps even to improve sleep efficiency in healthy people, may be a way to reduce the risk of Alzheimer’s. This is important toexplore further.”
The research appears Nov. 24 in The Journal of Experimental Medicine.
Brain plaques, which are mostly made of a protein called amyloid beta, accumulate in the brain before the onset of Alzheimer’s symptoms such as memory loss, personality changes and disorientation. These plaques continue to collect as the disease progresses. Scientists think that slowing or stopping this buildup could slow or stop the disease.
In the current study, the researchers worked with mice genetically engineered to develop a buildup of amyloid in the brain, which is characteristic of Alzheimer’s disease. When the researchers bred these mice with mice lacking the gene for orexin, their offspring slept longer and developed only half as many Alzheimer’s plaques, compared with the mice that had the orexin protein.
Orexin is made by cells in the brain’s hypothalamus that stimulate wakefulness.
“These cells have branches that carry orexin throughout the brain, and the protein acts like a switch,” said Holtzman, the Andrew B. and Gretchen P. Jones Professor of Neurology. “If you stimulate orexin production in sleeping mice, they wake up immediately.”
Low orexin levels are associated with narcolepsy, a condition marked by excessive sleepiness and frequent daytime sleeping spells. The mice with no orexin typically slept an extra hour or more during the 12-hour period when mice with orexin became more active.
When scientists reversed the experiment and artificially increased orexin levels throughout the brain, the mice stayed awake longer and developed more Alzheimer’s-like plaques.
But if the researchers changed orexin levels only in part of the brain – a change that did not affect the amount of time mice slept – plaque levels were unaffected.
“The fact that orexin can only affect plaques when it also affects sleep means we will have to think carefully about how to target it for Alzheimer’s prevention,” Holtzman said. “But the declines in plaque levels that we saw in the mice were very strong, so we’re still very interested in exploring its potential for reducing risk.”
He and his colleagues, including first author Jee Hoon Roh, MD, PhD, currently are studying the effects of sleep medications on amyloid beta production and plaque accumulation. The FDA recently approved Belsomra, the first sleep medication that affects orexin, and the researchers hope to assess it or similar drugs in the future.
This work was supported by the American Academy of Neurology Clinical Research Training Fellowship; the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (MSIP), 2013R1A1A1012925; an NRF MRC grant funded by the Korean government (MSIP), 2008-0062286; the Korea Institute of Science and Technology Institutional Program, 2E24242-13-110; grants 2014-0783, 2014-7203 and 2014-9077 from the Asan Institute for Life Sciences; an Ellison Medical Foundation Senior Scholar Award; the National Institutes of Health (NIH), P01NS074969, R01NS090934 and P30NS057105; the JPB Foundation; and the Cure Alzheimer’s Fund.
Roh JH, Finn MB, Stewart FR, Mahan TE, Cirrito JR, Heda A, Snider BJ, Li M, Yanagisawa M, de Lecea L, Holtzman DM. Potential role of orexin and sleep modulation in the pathogenesis of Alzheimer’s disease. The Journal of Experimental Medicine. Published online Nov. 24, 2014.
Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.
Brain networks break down similarly in rare, inherited forms of Alzheimer’s disease and much more common uninherited versions of the disorder, a new study has revealed.
Scientists at Washington University School of Medicine in St. Louis have shown that in both types of Alzheimer’s, a basic component of brain function starts to decline about five years before symptoms, such as memory loss, become obvious.
The breakdown occurs in resting state functional connectivity, which involves groups of brain regions with activity levels that rise and fall in coordination with each other. Scientists believe this synchronization helps the regions form networks that work together or stay out of each other’s way during mental tasks.
“The brain networks affected by inherited Alzheimer’s disease in a 30-year-old are very similar to the networks affected by uninherited Alzheimer’s disease in a 60-, 70- or 80-year-old,” said senior author Beau Ances, MD, PhD. “This affirms that what we learn by studying inherited Alzheimer’s, which appears at younger ages, will help us better understand and treat more common forms of the disease.”
The research appears online in JAMA Neurology.
According to Ances, the results show that functional connectivity may help scientists monitor the effects of treatment as patients progress through the transition between early disease and the first appearance of obvious symptoms.
“Right now, this period when functional connectivity begins breaking down is a time when family and loved ones may start noticing little changes in personality or mental function in someone with the disease, but not significant enough changes to cause real alarm,” Ances said. “The hope is that one day treatment already will be well underway before these sorts of changes begin — we want to slow or stop the damage caused by Alzheimer’s years earlier.”
Inherited Alzheimer’s disease can strike very early in life, causing symptoms in patients as young as their 30s or 40s. Identifying the mutations that cause these forms of the disease has helped scientists find proteins that become problematic in more common forms of Alzheimer’s, which typically appear decades later.
Researchers have long assumed that additional connections exist between inherited and uninherited Alzheimer’s disease, but until recently they have not had sufficient data to directly test many of those connections. Challenges have included the small number of people with inherited Alzheimer’s, and the slow development of both forms of the disease.
Scientists at the Charles F. and Joanne Knight Alzheimer’s Disease Research Center at Washington University began to tackle the first challenge five years ago by organizing the Dominantly Inherited Alzheimer’s Network (DIAN), an international network for identifying and studying families with inherited forms of the disease. The network now includes nearly 400 families.
To address the second challenge, Washington University researchers at the center have been gathering extensive health data on seniors through long-term projects such as the Healthy Aging and Senile Dementia Study, which is entering its 31st year.
These pools of data allowed Ances, an associate professor of neurology, to compare the effects of inherited and uninherited Alzheimer’s on functional connectivity. Scientists assess functional connectivity by scanning the brains of research participants while they daydream.
“The question was, where does the decline of functional connectivity fit in the whole picture of the development of Alzheimer’s disease?” Ances said. “And it clearly does have a place in the middle stages of the disease.”
That’s not the best place to look for an initial diagnosis, according to Ances. Ideally, scientists want to start treating Alzheimer’s disease as soon as possible.
“What this does tell us, though, is that functional connectivity may help us track the progression of Alzheimer’s in patients who are first diagnosed when they’re beginning to show early signs of dementia,” he said.
This work was funded by grants U19-AG032438 from the National Institute on Aging; K23MH081786 and R21MH099979 from the National Institute of Mental Health; R01NR014449, R01NR012657, and R01NR012907 from the National Institute of Nursing Research; P30NS048056, P50 AG05681, P01 AG03991, and P01 AG026276 from the National Institute of Neurological Disorders and Stroke; and G0601846 from the Medical Research Council. The study was also supported by the National Institute for Health Research Queen Square Dementia Biomedical Research Unit and the Washington University in St Louis Alzheimer’s Disease Research Center Genetics Core. Jack received grants R01-AG011378, U01-HL096917, U01-AG024904, RO1 AG041851, R01 AG37551, R01AG043392, and U01-AG06786 from the National Institutes of Health. Morris received grants P50AG005681, P01AG003991, P01AG026276, and U19AG032438 from the National Institutes of Health. Ourselin received grants EP/H046410/1, EP/J020990/1, and EP/K005278 from the Engineering and Physical Sciences Research Council; MR/J01107X/1 from the Medical Research Council; and FP7-ICT-2011-9-601055 from the EUFP7 project at the National Institute for Health Research University College London Hospitals Biomedical Research Centre High Impact Initiative.Thomas JB, Brier MR, Bateman RJ, Snyder AZ, Benzinger TL, Xiong C, Raichle M, Holtzman DM, Sperling RA, Mayeux R, Ghetti B, Ringman JM, Salloway S, McDade E, Rossor MN, Ourselin S, Schofield PR, Masters CL, Martins RN, Weinger MW, Thompson PM, Fox NC, Koeppe RA, Jack CR Jr., Mathis CA, Oliver A, Blazey TM, Moulder K, Buckles V, Hornbeck R, Chhatwal J, Schultz AP, Goate AM, Fagan AM, Cairns NJ, Marcus DS, Morris JC, Ances BM. Functional connectivity in autosomal dominant and late-onset Alzheimer Disease. JAMA Neurology, July 28, 2014.
New research shows that a common antidepressant may cut production of one of the chief suspects in the investigation of Alzheimer’s disease. These findings open a new avenue in the hunt for drugs to prevent the devastating brain disease.
It’s far too early for anyone worried about dementia to try citalopram, which is sold as Celexa. “This is not the great new hope. This is a small step,” cautioned Yvette Sheline of the University of Pennsylvania, who is leading the research with John Cirrito of Washington University in St. Louis.
Apr 26th 2014 | From the print edition
MANGANISM has been known about since the 19th century, when miners exposed to ores containing manganese, a silvery metal, began to totter, slur their speech and behave like someone inebriated. The poisoning was irreversible, and soon ended in psychosis and death. Nowadays workers are exposed to far lower doses and manganism is rare. But new research suggests it could be some way from being eradicated entirely. The metal’s detrimental effects on human health may be subtle but widespread, contributing to diseases known by other names.
For the past ten years Brad Racette, a neurologist at Washington University in St Louis, Missouri, has been tracking those effects, paying special attention to welders, since they are exposed to more manganese than most people. Being harder than iron, manganese is often used to strengthen steel and is present in many industrial emissions, including welding fumes.
In one study, Dr Racette found that symptoms resembling Parkinson’s disease (PD) were 15% more prevalent in welders than in other kinds of workers. In another, he found that in a small sample of welders who had not yet reported any neurological symptoms, brain scans showed signs of damage to a part of their brains called the striatum that co-ordinates movement and is damaged in PD. In the case of PD, it has been clearly shown that the first symptoms appear only after the striatum has lost more than half of its neurons.
These findings were controversial, and not just with the industries that make use of manganese. Though most neurologists agree that manganese poisoning and PD have a lot in common, others have found that the pattern of damage in the brains of PD patients and those exposed to high levels of manganese differs in important ways. The differences are reflected, Dr Racette’s critics say, in the fact that PD responds well to the drug L-dopa—a chemical precursor of dopamine, the neurotransmitter that patients lack because the brain cells that make it gradually die—whereas L-dopa does nothing for those with manganese poisoning.
This debate matters because on it rests the question of whether manganese in the environment could be one cause of PD—a disease that affects a significant fraction of the general population, not just manganese-exposed workers. Around 60,000 Americans are diagnosed with PD each year. In a 2010 survey, Dr Racette’s group found that PD was between two and ten times more common in the American Midwest and north-east—where industrial manganese emissions are highest—than in western and southern regions.
That was a dramatic finding, but it was only a correlation and not proof of a causal link. Now, however, Dr Racette thinks he has found the ideal population in which to search for that link. Some 80% of the world’s known high-grade manganese ore lies beneath the desert of South Africa’s Northern Cape Province, where it is mined. But South Africans also mine for other things, including gold and diamonds. For the past 100 years a national scheme has provided free heart-and-lung autopsies on dead miners, and compensation to their families if these reveal mining-related diseases such as mesothelioma.
About five years ago Dr Racette’s group persuaded the scheme’s organisers to include miners’ brains in the autopsies, and with Gill Nelson, an epidemiologist from Witwatersrand University in Johannesburg, and others he has now studied over 60 of them. The first results, published in Neurotoxicology late last year, suggest that those who were exposed to manganese had lost significantly more grey matter from the striatum than those who were not. Interestingly, says Dr Racette, the miners are on average exposed to less manganese than welders are in the United States.
The number of brains autopsied is still too small to provide convincing evidence that manganese causes PD. But Dr Racette says the miners’ brains could anyway reveal a lot about what does cause PD. They show signs of inflammation, for example; one theory holds that PD involves an inflammatory reaction in the brain.
Either way, it is now clear that exposure to high levels of manganese is not good for the brain. But what constitutes a high level? As a trace element in people’s diet, manganese is essential to keeping organs, including the brain, healthy. The American standard for the airborne concentration of manganese dust is now 5 milligrammes per cubic metre of air—a vast improvement on the doses of close to 1,000mg/m3 that some workers were exposed to only 60 years ago. Last year, Robert Park, a statistician with America’s National Institute for Occupational Safety and Health, published a review which concluded there was good evidence of neurological effects at concentrations lower than 0.2mg/m3.
Manganese is not the only toxin in industrial emissions whose effects on human health are not properly understood. Such controversies will continue.
The symposium will be from 9 a.m. to 5 p.m. at the Eric P. Newman Education Center.
Its keynote speakers will be Sean Morrison, PhD, director of the Children’s Medical Center Research Institute, the Mary McDermott Cook Chair in Pediatric Genetics at the University of Texas Southwestern, and a Howard Hughes Medical Institute investigator; and Jonathan A. Epstein, MD, the William Wikoff Smith Professor of Cardiovascular Research, chair of the Department of Cell and Developmental Biology and scientific director of the Penn Cardiovascular Institute at the Perelman School of Medicine at the University of Pennsylvania.
Morrison will discuss the impact of the NF1 gene on stem cell function in the developing brain, while Epstein will present data from fish models that reveal important roles for the NF1 gene in heart development.
Of the three forms of NF, NF1 is the most common, affecting 1 in 2,500 individuals worldwide. There is no cure for NF1, and its effects are difficult to predict.