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.
Increased brain cell activity boosts brain fluid levels of a protein linked to Alzheimer’s disease, according to new research from scientists at Washington University School of Medicine in St. Louis.
Tau protein is the main component of neurofibrillary tangles, one of the hallmarks of Alzheimer’s disease. It has been linked to other neurodegenerative disorders, including frontotemporal dementia, supranuclear palsy and corticobasal degeneration.
“Healthy brain cells normally release tau into the cerebrospinal fluid and the interstitial fluid that surrounds them, but this is the first time we’ve linked that release in living animals to brain cell activity,” said senior author David M. Holtzman, MD. “Understanding this link should help advance our efforts to treat Alzheimer’s and other neurodegenerative disorders associated with the tau protein.
The study appears online in The Journal of Experimental Medicine.
Tau protein stabilizes microtubules, which are long columns that transport supplies from the center of the cell to the distant ends of the cell’s branches. Some tau in the cell is not bound to microtubules. This tau can become altered and clump together inside brain cells, forming structures called tangles. Scientists have tracked the spread of these clumps through brain networks in animal models.
“In Alzheimer’s disease, you first see clumps of tau in a region called the entorhinal cortex, and then in the hippocampus, and it continues to spread through the brain in a regular pattern,” said Holtzman, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology. “In another disorder, supranuclear palsy, tau clumps first appear in the brain stem and then spread to regions that the brain stem projects to.”
These regular patterns of tau spread through brain networks have led scientists to speculate that dysfunctional tau travels to different brain regions via synapses — the areas where individual nerve cells communicate with each other.
Holtzman’s results support this hypothesis, showing that when nerve cells “talk” to each other, tau levels go up in the fluids between those cells, suggesting that brain cells are secreting tau when they send signals.
So far, the researchers only have been able to measure single copies of tau in brain fluid, not the tau clumps. They are looking for a way to detect the clumps. If brain cells can secrete and take in clumps of tau, the scientists believe, these clumps may cause previously normal tau in the receiving cell to become corrupted, fostering the spread of a form of tau involved in disease.
“We also want to know whether brain cells are secreting tau as waste or if tau has a function to perform outside the cell,” Holtzman said. “For example, there have been hints that tau may modulate how easy or difficult it is to get brain cells to communicate with each other.”