It has long been known that occupational lead exposure has negative effects on nerves and a number of areas of brain functioning. Certain well-ingrained brain functions, however, seem resistant to the effects of lead exposure. One of these is reading ability, which is also an indicator of cognitive reserve, or the brain's ability to maintain function in spite of damage. Genetics, education and childhood cognitive abilities are factors which may contribute to cognitive reserve.

The study involved 112 smelter workers in New Brunswick, Canada. The workers underwent several cognitive and motor speed tests and a measure of reading ability. The researchers calculated working lifetime lead exposure from historic blood lead levels obtained by the smelter. The workers were then divided into groups with high cognitive reserve, defined as a reading level of 12th grade or higher, and low cognitive reserve, a reading level of 11th grade or lower.

"Even though the two groups had similar lead exposure, the cognitive effects of lead were 2.5 times greater in workers with low reading ability. In contrast, the effect of lead on motor speed was comparable in both groups as cognitive reserve does not apply to motor speed," said study author Margit L. Bleecker, MD, PhD, with the Center for Occupational and Environmental Neurology in Baltimore, MD, and member of the American Academy of Neurology. "This suggests that high cognitive reserve has a protective effect that allowed these workers to maintain their functioning, even though lead affected their nervous system as shown by its effect on their motor skills."

Bleecker says there are multiple theories on how cognitive reserve protects against insults to the brain. "These include an increased concentration of cortical synapses in larger brains that provide more brain capacity, a greater ease of using alternative brain circuits, and the ability to process tasks more efficiently in current brain circuits," said Bleecker.

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But the real breakthroughs came through collaboration. Hauser said that individually, none of the six centers in the consortium could have completed a study of this scale and complexity, but by using a Collaborative Research Award from the National MS Society, they were able to form a truly effective international consortium that could deliver the most exhaustive search for MS risk factors ever published.

The consortium paper is among a series of recent whole-genome association studies that have begun to uncover the genetic basis of complex diseases like diabetes, schizophrenia, and coronary artery disease. Unlike diseases caused by a mutation in a single gene, these conditions seem to arise from a combination of genetic, behavioral and environmental factors.

Jorge Oksenberg, PhD, a UCSF neurology professor who has been involved in the development of the UCSF collection for more than a decade, said that it wasn't until scientists were able to combine the potential of both repositories with the intellectual and financial resources of previously competing research teams that they were able to make the connections represented in these studies.

"For studying these complex genetic diseases, where we're looking at many genes contributing and each one contributing just a little bit, we need a very large group of patients and controls," said Oksenberg, who, along with Hauser, worked on both the consortium research and the study for the "Nature Genetics" paper. "We're looking for genetic markers that we know are common in the population at large, but they're somehow more common in the MS patients, and when combined, they make the patient more susceptible to getting MS."

Genomic technologies have now made it possible to uncover these subtle genetic associations. The next step is to begin to collect larger numbers of samples and examine more DNA sequences, which will allow scientists to identify subtler variations that contribute to the disease.

"Despite all the hype and new technology, the genome is still mysterious to us," Oksenberg said. "This has opened a new window into MS genetics. Now we need to understand what these chains are doing."

The international collaboration is currently planning even larger and more detailed explorations of the genetic landscape of MS and is now committed to making the entire data set available to MS researchers worldwide.

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