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| Elliott J. Mufson |
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Rush-Presbyterian-St. Luke's Medical Center, Department of Neurological Sciences, Chicago, IL 60612, USA
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Presentation: |
| 2002-10-06, 12:50-13:30 |
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| Human Cholinergic Basal Forebrain: Chemoarchitecture, Connectivity, Chemistry and Neurologic Disease. |
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| For over thirty years it was believed that one of the major deficits in people with Alzheimer's disease (AD) was the loss of cell bodies located deep in the brain, which contain the chemical to acetylcholine, which is needed to transmit information throughout the brain. These brain cells are found deep within the brain in a region known as the nucleus basalis and septal region and provide the major cholinergic connections to an areas of the brain related to cognitive function including the outer covering of the brain or cortex and the hippocampus. We have been studying these region for several years using various techniques to determine their location, changes due to age and disease and ultimately to discover how to prevent the loss of these cholinergic neurons. To investigate the fate of this brain region, we are fortunate to have a program composed of retired catholic clergy who have agreed to behavioral testing for mental status beginning at the age of 65 years and eventual donation of their brain for pathological study. These people fall into three clinical categories: 1) AD, 2) mild cognitive impairment without AD and 3) no cognitive impairment. Using material from this group of people we found that the cholinergic cells are located in several different brain regions and that they are dependent for their survival on a growth promoting substance called nerve growth factor (NGF). In fact, these cells produce the receptors or docking devices needed to transport NGF back to these cell bodies for their maintenance and survival. In advanced AD there are severe deficits in all aspects of this trophically supported system including loss of neurons, decrease of NGF int hese cell bodies and a reduction in levels of cholinergic activity in the cortex and hippocampus. It was believed that these cells die early in the onset of AD. To the contrary, we have found that in brains obtained from retired clergy, that these brain cells are preserved in the early stages of the this disease as well as in people with mild cognitive impairment without AD. Even more interesting is our observation that the is an increase in the level of the cholinergic synthesizing enzyme choline acetyltransferase in the hippocampus. These findings suggest that early in the onset of mental deterioration that select cholinergic mechanisms are stable and in fact undergo a unique up-regulation in the face of aging and the onset of dementia. This observations indicate that drug therapies aimed at the preservation of cholinergic mechanisms may be a viable treatment strategy for early AD and mild cognitive impairment in the elderly. |
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