PITTSBURGH, Jan. 31 - A study out of the University of Pittsburgh has uncovered a completely different mechanism behind mild cognitive impairment (MCI), an increasingly common memory problem that is thought to be a precursor to Alzheimer's disease (AD). The results are surprising even to the researchers conducting the study and may explain why current medications don't improve memory function effectively. Further, the findings may redirect research into many of the newer treatments designed to prevent memory problems.
The study, published in today's Annals of Neurology, found that in older people with MCI, the brain produces more choline acetyltransferase (ChAT), an enzyme that is important in memory and cognitive functions. The researchers believe this is the brain's attempt to maintain normal function as the neurons that form communication lines to the brain's memory center die. Strengthening their finding are autopsy results showing more than 60 percent of people who had MCI within a year before they died already had evidence of neurodegeneration that is seen in the early stages of AD.
The results are almost the opposite of what most researchers believed - that a decrease in ChAT levels causes MCI - the theory behind today's most popular Alzheimer's treatments, which include drugs meant to boost levels of the enzyme's product, the neurotransmitter acetylcholine (ACh).
"Because we thought deficits in ChAT were responsible for memory problems in patients with MCI, the most common treatment we use is a class of drugs called cholinesterase inhibitors that help the brain produce more," said Steven T. DeKosky, M.D., professor of neurology, psychiatry, neurobiology and human genetics at the University of Pittsburgh School of Medicine and principal investigator of the study. "These results suggest that the brain increases production of ChAT on its own in people with MCI and that in addition to their use in early AD, these drugs may be effective if used in patients who have a deficit in ChAT - those with advanced AD.
"These findings suggest we should spend more time researching ways to slow down or stop the early stages of neurodegeneration," added Dr. DeKosky.
Dr. DeKosky and colleagues from the University of Pittsburgh and Rush Presbyterian-St. Luke's Medical Center in Chicago studied the brains of nuns, priests and brothers participating in the Religious Orders Study (ROS), which is based at the Rush Alzheimer's Disease Center. The participants had all been diagnosed as being either normal, having mild cognitive impairment or having Alzheimer's disease within a year of death.
AD researchers had long believed memory and cognitive problems associated with MCI were caused when levels of ChAT in the cortical and hippocampal areas of the brain fell. ChAT is necessary to form the chemical ACh, which serves as a messenger carrying information between neurons to the hippocampus, where new memories are formed and stored. In this study, the first to report levels of ChAT in the hippocampus of humans with very mild AD and MCI, they found ChAT levels were actually increased in people with MCI, but returned to normal levels in people with early-stage AD. Only people with end-stage AD had ChAT levels below normal.
Autopsies revealed that memory problems in people with MCI most likely are caused by neurodegenerative processes that occur very early in the process that leads to AD, even before clinical signs are present. Specifically, brains of people with MCI were experiencing dysfunction and death of neurons in the entorhinal cortex (ERC), causing interference with the ability of the hippocampus to get information from the rest of the brain about what it is supposed to remember.
"If you compare the human brain to a computer, the hippocampus can be thought of as the brain's random access memory (RAM) chip," explained Dr. DeKosky. "The death of neurons from the entorhinal cortex to the hippocampus would be akin to breaking the connection between the computer's RAM and the rest of the motherboard." This ERC cell loss, not the cholinergic deficit, appears responsible for the early memory changes in MCI and mild AD.
According to Dr. DeKosky, the increase in ChAT in MCI demonstrates the brain's ability to compensate in one area for deficits in another to try to maintain normal function. As the disease progresses, the brain eventually loses that battle and levels return to normal, then decrease as the disease moves into its final stages.
More than 900 older Catholic clergy from 40 groups across the United States are participating in the Religious Orders Study. All participants have agreed to annual memory testing and brain donation at the time of death. Both Rush and Pitt researchers express their deep appreciation to the study participants for their dedication and altruism. The study is funded by the National Institute on Aging.
Other researchers involved in the study are: Milos D. Ikonomovic, M.D. and Scot D. Styren, Ph.D., both of the Alzheimer's Disease Research Center, University of Pittsburgh School of Medicine; Laurel Beckett, Ph.D., David Bennett, M.D., E.J. Cochran, M.D., Jeffrey H. Kordower, Ph.D., and Elliott J. Mufson, Ph.D., all of the department of neurological sciences and Alzheimer's Disease Center, Rush-Presbyterian-St. Luke's Medical Center; and Stephen Wisniewski, Ph.D., of the University of Pittsburgh Graduate School of Public Health.
John M. Pontarelli
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