Paper du Jour: Ikonomovic MD, Mufson EJ, Wuu J, Cochran EJ, Bennett DA, DeKosky ST. Cholinergic plasticity in hippocampus of individuals with mild cognitive impairment: Correlation with Alzheimer's neuropathology. J Alzheimers Dis 2003 Feb;5(1):39-48. (Abstract)

Glenda Bishop, with Steven T. DeKosky and Milos Ikonomovic, led this live discussion on 19 May 2003. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

View Transcript of Live Discussion — Posted 26 August 2006

Background Text
By Glenda Bishop, Case Western Reserve University, Cleveland, Ohio

In this study, Ikonomovic and colleagues sought to determine whether there is a correlation between the pathological lesions of AD and upregulation of the cholinergic system in the hippocampus. To do this, they investigated patients in four clinical categories: no cognitive impairment (NCI), mild cognitive impairment (MCI), mild AD, and late AD, as determined by MMSE scores and the NINCDS/ADRDA clinical criteria. This study includes data from their previous longitudinal Religious Orders Study (see ARF related news story), as well as new data from a patient cohort from the University of Pittsburgh Alzheimer's Disease Research Center.

The activity of choline acetyltransferase (ChAT) in the hippocampal grey matter was lowest in late-AD patients, and highest in patients with MCI. Pathological staging with Braak criteria showed a wide range of Braak stages in each group of patients even when the MMSE scores were comparable. Further breakdown of each clinical group into the different Braak stages revealed that the observed differences in ChAT activity was most robust in patients that were Braak stage III/IV. The authors then examined each of the pathological lesions of AD and found a positive correlation between hippocampal ChAT activity and both neuritic and diffuse plaques in the entorhinal cortex. Greater plaque densities were associated with higher ChAT activities. In the hippocampus, only neuritic plaques correlated with ChAT activity. However, there was no correlation between hippocampal ChAT activity and neurofibrillary tangles in either the entorhinal cortex or hippocampus.

Ikonomovic and colleagues have proposed that there is an entorhinal-hippocampal disconnection that leads to the short-term memory impairments seen in MCI, rather than any cholinergic dysfunction that has previously been demonstrated in late AD. They suggest that increased cholinergic activity in MCI is a compensatory mechanism, which eventually fails as the pathology progresses and AD develops.

Points for discussion:

• If increased cholinergic activity is indeed an early compensatory mechanism, what implications does this have for current prescription guidelines for AChE inhibitors? Should they be given at the MCI stage to support and prolong this compensatory process?
• Let's turn this around: Since MCI has increased cholinergic activity, and mild AD has cholinergic activity comparable to noncognitively impaired patients, should AChE inhibitor treatment begin only after the clinical symptoms of AD have progressed further and cholinergic activity clearly diminishes? Can practicing neurologists draw any lessons from this work?
• How representative is ChAT activity of the overall functioning of the cholinergic system? What other markers of the cholinergic system are available for study, and do we expect that they would follow the pattern seen here with ChAT activity?
• ChAT activity was positively correlated with Aß deposition. Does this suggest that activity of the cholinergic system is upregulated by Aß (or as a response to Aß deposition), or does increased cholinergic activity cause Aß to deposit? Alternatively, is it possible that these two events are independent of each other?
• It has been shown that administration of donepezil to older pilots improves their performance in a flight simulator (see ARF related news story). This corresponds with the idea that increased activity in the cholinergic system in MCI occurs in order to compensate for an impending decrease in cognitive function. Does this mean these drugs could be taken as cognitive enhancers. Should they? Is this dangerous?
• How would you test the hypothesis that entorhinal-hippocampal disconnection stimulates increased activity of the cholinergic system? Are there animal models that can demonstrate this idea? And how would that disconnect occur?

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