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Different forms of Alzheimer’s have similar effects on brain networks

 August 26, 2014

By Michael C. Purdy

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.

 

Ances

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. 

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.

Study: A common antidepressant may cut Alzheimer’s protein

By Associated Press, Published: May 19

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.

continue story at WashingtonPost.com>>

Manganese poisoning

Subtle effects

Exploring the link between manganese and Parkinson’s disease

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.

The level of harm

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.

From the print edition: Science and technology

NF symposium to focus on tumor disorders

April 24, 2014
By Michael C. Purdy
A diagnosis of neurofibromatosis (NF) introduces many uncertainties to children and their parents. Patients affected by these conditions are prone to developing benign and malignant tumors as well as learning and attention impairments, reduced physical coordination, seizures, headaches, scoliosis, bone deformities, cardiovascular problems and loss of hearing and sight.
Washington University School of Medicine in St. Louis is home to an internationally renowned center for multidisciplinary research of NF and comprehensive care of patients affected by it. Established in 2004 by David H. Gutmann, MD, PhD, the Donald O. Schnuck Family Professor of Neurology, the university’s Neurofibromatosis Center focuses on accelerating the pace of scientific discovery and applying that research to the care of children and adults with NF.

Gutmann
Gutmann and other center leaders will host and be among the presenters at the Washington University Neurofibromatosis Center Symposium on May 16, which will bring patients, their family members and researchers from across the nation to the Medical Campus to learn about and discuss the latest insight into the diagnosis and treatment of NF.

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.

There is no charge to attend the symposium, but those interested in attending are encouraged to register online by May 2. For more information, email brouilletk@neuro.wustl.edu.