Summary

This Live Journal Discussion is the first in a series of upcoming discussions of selected articles in the Journal of Alzheimer's Disease, which is making the full text (.pdf) of these papers available to Alzforum for this purpose.

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.

Transcript:

This live discussion with authors Steven T. DeKosky and Milos Ikonomovic was led by Glenda Bishop on 19 May 2003. This Live Journal Discussion was the first in a series of upcoming discussions of selected articles in the Journal of Alzheimer's disease, which is making the full text of these papers available to Alzforum for this purpose.

Participants: Steven DeKosky, University of Pittsburgh; Milos Ikonomovic, University of Pittsburgh; Elliott Mufson, University of Illinois at Chicago; Glenda Bishop, Case Western Reserve University; Keith_Crutcher, University of Cincinnati; Gabrielle Strobel, ARF; Jim Geddes, University of Kentucky; Robert Bowser, University of Pittsburgh; LJ Sparvero, University of Pittsburgh; Vassilis Koliatsos, Johns Hopkins University; Changiz Geula, Harvard Medical School; Stephen Ginsberg, Nathan Kline Institute, NYU School of Medicine; Li Liu, University of Kupio, Finland; Larry Nault, Consultant listed in Forum profile; Alexei Koudinov, Russian Academy of Medical Sciences.

 

Note: The transcript has been edited for clarity and accuracy.

Glenda Bishop
I am Glenda Bishop from Case Western Reserve University, and I will be the moderator today. Welcome to our authors, Steven Dekosky, Milos Ikonomovic, and Elliott Mufson, and to everyone else, too.

Milos Ikonomovic
Hi all.

Glenda Bishop
I guess we should get started. One of the most interesting things I found about the paper in question was the report of increased cholinergic activity in early Alzheimer's disease (AD).

Milos Ikonomovic
It was in mild cognitive impairment (MCI).

Glenda Bishop
Were you surprised to see this in MCI?

Vassilis Koliatsos
Milos, we need to be a bit noncommittal here.

Steven DeKosky
Well, the increase was in levels of the synthetic enzyme, not necessarily cholinergic activity....

Robert Bowser
And that's enzymatic activity, not necessarily enzyme levels.

Gabrielle Strobel
Steven, don't we generally assume that one means the other. Too much of a leap?

Steven DeKosky
Yes, too much of a leap. ChAT (choline acetyl transferase) is not the rate-limiting step.

Changiz Geula
Steve and Milos, do you think that a similar cholinergic compensation occurs in the neocortex but that it is masked by an age-related decrease?

Steven DeKosky
We did see the increase in the frontal cortex, reported it in the paper, but do not have as elegant a sprouting mechanism as is known in the hippocampus.

Milos Ikonomovic
We were not surprised so much because of previous reports of cholinergic sprouting after entorhinal lesion. That happens in the hippocampus, so we are glad it showed up there, but there is also an increase (less so) in the frontal cortex.

Vassilis Koliatsos
The choline transporter (sodium-dependent high-affinity choline uptake system, or SDACU) is the rate limiting step, although ChAT activity tells you a lot about the terminal situation in central cholinergic systems. ChAT is a GOOD marker of sprouting, based on my experiments with NGF.

Milos Ikonomovic
Yes, acetylcholine esterase (AChE) also.

Jim Geddes
Steve and Milos, one of the intriguing findings from your study is the increase in ChAT in MCI, then decline in AD. Does this suggest caution with the use of AChE inhibitors?

Steven DeKosky
No, I think the need for and the success of the esterase inhibitors are facts. There is probably hypofunction of the cholinergic system, as shown by the sensitivity to scopolamine in AD subjects (Sunderland et al. 1995). I think this shows the drugs may be even more effective in later disease when you do lose available ChAT....

Jim Geddes
Steven, but could it lead to faster loss of the cholinergic neurons?

Glenda Bishop
Is ChAT the best marker to use for looking at cholinergic functioning? Or could someone make a better suggestion?

Steven DeKosky
ChAT and AChE are the most stable (postmortem) markers of the cholinergic system. That is why they are suitable.

Milos Ikonomovic
I think ChAT is one good option we have, but we should think about vesicular ACh transporter (VAChT) and high-affinity choline uptake (HACU).

Glenda Bishop
Milos, what advantages would VAChT and HACU have?

Milos Ikonomovic
These markers should tell us more about what's happening with ACh at synapses.

Changiz Geula
Why do you invoke an entorhinal input in terms of the compensation? It can also be explained in terms of early cholinergic loss or underactivity.

Steven DeKosky
Changiz, the conclusion about sprouting was based on the Braak scores showing that the ChAT increase correlated strongly with the stage at which the entorhinal cortex (ERC) was severely impaired.

Stephen Ginsberg
Steven, Milos, do you think that the cortical sprouting is local (intrinsic) or coming from the basal forebrain?

Vassilis Koliatsos
It could ONLY come from the basal forebrain. More than 90 percent of cortical cholinergic innervation in primates is extrinsic.

Milos Ikonomovic
Stephen, we think it's coming from septum/diagonal band neurons.

Changiz Geula
There is cortical sprouting of axons in the cerebral cortex, which is considerably enhanced in AD. However, the sprouting is not normal. The terminals are ballooned, thickened and abnormal. Thus, sprouting does take place, but probably normal transmission does not.

Vassilis Koliatsos
Changiz, I am not sure this is the only way to think about it.

Robert Bowser
Steven, Milos, while we know sprouting can occur in AD, have you been able to demonstrate any evidence of sprouting (histologic) in the MCI cases that have increased ChAT activity?

Milos Ikonomovic
Robert, that's a good question; our preliminary data suggest a decrease of AChE staining.

Changiz Geula
Steve, Braak scores also correlated with tangles in the basal forebrain. It would be hard to conclude which is the cause.

Vassilis Koliatsos
Well, Braak 3/4 tells you about degeneration in ERC and cholinergic sprouting could be reactive synaptogenesis à la Gary Lynch and many others. This is the phenomenon by which afferent systems unaffected by the lesion (in this case, the cholinergic system from the medial septum) expand their terminals to occupy sites deserted by degenerating terminals from the cortical ERC input. This is the most plausible explanation.

Steven DeKosky
I don't agree.... Tangles in basal forebrain don't suggest those cells would sprout. And they would have to sprout into...what? The animal studies of sprouting after ERC lesion was the basis for our hypothesis....

Vassilis Koliatsos
I agree with this statement.

Milos Ikonomovic
I'd say Braak 3/4 tells you not only about the ERC, but also about the hippocampus. That's why it was important to see ChAT going up in those people, when the hippocampus starts to undergo neurodegeneration changes.

Vassilis Koliatsos
Milos, the only problem is that ChAT goes up mostly in Ammon's horn, whereas sprouting in animals is mostly in the dentate gyrus.

Glenda Bishop
Milos and Steve, do you plan to look at any of these other markers of the cholinergic system, or are they so unstable postmortem that they would not be terribly accurate?

Gabrielle Strobel
For those of us who are less expert: What causes the sprouting? Ab deposits?

Vassilis Koliatsos
Gabrielle, Ab deposits are unlikely to have caused the sprouting. See our paper in J Neuroscience in November (Sheng et al., 2002).

Milos Ikonomovic
Sprouting is probably caused by ERC lesion—that's what Jim and Brad can tell us more about, in animal studies.

Steven DeKosky
Not in our study; it was full cross-section in the analyses.

Jim Geddes
Both the sprouting and ChAT loss do not appear to be the result of Ab deposits, based on results obtained in animal models. I agree that the sprouting is the result of neuron loss in entorhinal cortex.

Changiz Geula
The fact remains that sprouting of the cholinergic axons in the cortex has been consistently reported and we have evidence that this "abnormal" sprouting shows a continuous increase in the course of aging and AD.

Vassilis Koliatsos
Changiz talks about a very different type of sprouting than the one observed after entorhinal lesions.

Changiz Geula
Vassilis, that is true. And this type occurs in neocortex as well. Unless one looks at ChAT activity at various subsectors of the hippocampus, we won't know if the increase in activity is due to loss of entorhinal input.

Vassilis Koliatsos
 Absolutely.

Milos Ikonomovic
Changiz, that's exactly what we are doing.

Milos Ikonomovic
Jim, I agree, even though we saw a correlation with neuritic plaques in the ERC and the hippocampus...but that may be related more to dystrophic neurites than amyloid in these plaques!

Steven DeKosky
Nevertheless, our chemical ChAT studies are not able to detect the histological differences.... It would help to know if the same sprouting, Changiz, is seen in the temporal or parietal cortex, where we didn't see an increase in ChAT....

Changiz Geula
Steve, The abnormal sprouts do occur in many cortical areas.

Vassilis Koliatsos
Changiz, you do not know whether its tons of ChAT sequestered in axonal abnormalities or ChAT freshly shipped to newly sprouted axons.

Steven DeKosky
We are looking at the sub-areas now. We will answer that question. Again, the reason we made the proposal was extrapolation from animal studies and the fact that the Braak scores pointed the finger at demise of the lamina II neurons.

Vassilis Koliatsos
So, we all agree here.

Jim Geddes
Changiz, Steven, and Milos, it would be interesting to look at the morphology of sprouting neurons in the transgenic mouse APP models combined with an entorhinal lesion. It's an old hypothesis, but the Ab may be contributing to an aberrant sprouting response.

Changiz Geula
Jim. That is a great idea.

Milos Ikonomovic
Jim, that's very interesting and we'd like to do that.

Vassilis Koliatsos
Jim, see our paper in J Neuroscience in November (Sheng et al., 2002). (See also ARF related news story).

Glenda Bishop
Vassilis, what does that paper show?

Vassilis Koliatsos
Loss of Ab deposits after disruptions of the perforant system ALONG with sprouting of cholinergic fibers in the outer half of the molecular dentate layer in APPswe mice. Plaque deposition may be a dynamic balance between shipment of mutated APP and more cleansing by glial cells, and other, largely unknown, synaptic modifications.

Changiz Geula
Based on our findings, which are being submitted for publication, the sprouting may relate more to cholinergic neuronal abnormalities. We find that these neurons show tangles very early, sometimes in ages of 20s or 30s, and that tangles here increase consistently in aging and AD.

Glenda Bishop
Milos, you say that neuritic plaques are correlated with ChAT activity. Why do you not think that it could be related to the amyloid within them?

Milos Ikonomovic
I'm not saying amyloid has no role. It just makes more sense that neuritic pathology is involved, because of good correlation with Braak scores.

Milos Ikonomovic
Vassilis, have you seen the plaque loss restricted to the hippocampus, or did you see it in cortical areas, as well?

Vassilis Koliatsos
Milos, dentate gyrus mostly, much less so in polymorph of dentate, NOTHING in CA.

Gabrielle Strobel
Milos and Steven, I did not understand clearly in the paper whether hippocampal/ERC tangles correlated with ChAT activity at the MCI/AD transition? No?

Milos Ikonomovic
Gabrielle, we didn't do stereological counting of ERC's neurofibrillary tangles (NFTs). We'll do that in future experiments.

Alexei Koudinov
It's possible that Ab is involved specifically in recovery for cholinergic terminals. See previous discussion and JNS article by Lazarov (Nov 2002).

Vassilis Koliatsos
I do not think that we know that Ab has anything to do with sprouting.

Milos Ikonomovic
Vassilis, that's very interesting. So, no cortical reductions in your model?

Vassilis Koliatsos
It was after ERC and perforant path lesions. So, nothing in neocortex.

Robert Bowser
Vassilis, so can the animal studies be compared properly to the human AD studies, since the sprouting is occurring in different locations and by different neuronal cell types.

Vassilis Koliatsos
Bob, I think we can reasonably extrapolate. ERC to dentate system is very similar in all mammalian species, but we cannot know for 100 percent, of course.

Milos Ikonomovic
Vassilis, are you checking that effect after longer time points?

Vassilis Koliatsos
Milos, we checked after one month, Sam Sisodia checked at three months, and it's the same effect.

Milos Ikonomovic
Vassilis, we need to measure ChAT in the hippocampus of those mice!

Changiz Geula
Vassilis and Milos, I agree that A-b may be minimally involved. As I mentioned, the cortical sprouting relates to cholinergic neuronal tangles. Furthermore, the sprouting is not associated with plaques.

Stephen Ginsberg
Has there been an attempt to remove cholinergic inputs (e.g., fimbria-fornix transection and/or excitotoxic lesions of nucleus basalis) in the APP mice?

Steven DeKosky
I think these are all fascinating and heuristic possibilities. In the end: There is a known relationship of ERC denervation and upregulation/sprouting of cholinergic fibers. All of the mechanisms are possible. What I have difficulty with is the suggestion that it is something other than the ERC lesion-induced sprouting that is responsible. We need a mechanism whereby tangles would cause upregulation of, eg., ChAT, when they generally downregulate everything intrinsic....

Changiz Geula
Steve, compensatory sprouting by nontangle-bearing neurons is a distinct possibility.

Steven DeKosky
Changiz, it's a possibility. Might be useful to look in tangle-only diseases (FTD, PSP, etc.) at CBF neurons and see if they have excess ChAT....

Vassilis Koliatsos
Milos, this would be a nice interpretative adjunct to your paper.

Gabrielle Strobel
Steve and Milos, what is it that disrupts the perforant pathway? Or ERC-hippocampal connections...?

Milos Ikonomovic
Death of stellate neurons in layer II ERC.

Stephen Ginsberg
Milos, the stellate cells also bear NFTs and need to be factored into the equation, right?

Milos Ikonomovic
Steve, that's right. That's why we need to count NFTs there and correlate with sprouting/cholinergic changes.

Gabrielle Strobel
Milos, about the death of the stellate neurons in ERC layer II: So you think the problem is cell death, not a process starting at the terminal, i.e., synaptic dysfunction, degeneration, and retrograde loss of the neuron?

Milos Ikonomovic
Gabrielle, yes, I think so, and not only cell death, as Steve pointed out, NFTs, and even earlier changes leading to NFT formation.

Glenda Bishop
Milos and Steven, what do you think the implications of your study are for treatment of AD with cholinesterase inhibitors? Should we give them earlier to try to take advantage of the compensatory response that you have seen in MCI?

Milos Ikonomovic
Glenda, yes, they should be given early, and there are already encouraging results with them (donepezil) in MCI.

Gabrielle Strobel
Milos, is there a citation for this or are these unpublished results?

Milos Ikonomovic
Gabrielle, this was presented by Steven Salloway at the AAN meeting in April.

Vassilis Koliatsos
AChE inhibitors should be given early, but Milos's paper is only one of the (possible) reasons.

Steven DeKosky
All, there are no proven effects of AChE inhibitors in MCI. There are four studies underway; there are no results other than a very short-term set of data from Pfizer in Hawaii last month.

Jim Geddes
Vassilis, getting back to the entorhinal lesion experiments: I think we're talking about different experiments. Have you looked at the sprouting of cholinergic fibers in mutant hAPP mice, in which hippocampal Ab deposits have formed prior to the EC lesion?

Glenda Bishop
Vassilis, what other reasons are there for giving AChEIs early?

Changiz Geula
All, there are a number of studies with AChEIs in MCI which are ongoing and some have actually produced encouraging preliminary results.

Vassilis Koliatsos
There are some indirect data from Jennsen and Novartis that early treatment may afford greater benefits than late treatment in AD.

Steven DeKosky
Hold on here. There are NO data that show any strong effects in MCI. A six-month exposure to patients did not show much.... The studies in MCI on Aricept, Reminyl and Exelon are still underway, still double-blinded....

Vassilis Koliatsos
Many of us use anticholinesterases in our patients with early AD and most of us are very encouraged. It is important to say that, at this point, this is clinical lore alone.

Glenda Bishop
Vassilis, but that is early AD; would it be effective in MCI?

Steven DeKosky
We won't settle here today whether amnestic MCI is early AD or not, or whether there is an effect of these meds early.

Vassilis Koliatsos
MCI is like dropsy, could be AD, could be Parkinsonism plus, could be vascular.

Gabrielle Strobel
When such treatment changes become clinical practice quickly, they become difficult to test because all patients want the drugs early. Are clinicians jumping the gun, Steven?

Vassilis Koliatsos
MCI is a term that needs to be overcome with further prospective studies and biological markers.

Steven DeKosky
By early, I mean in MCI.... Amnestic MCI, though, is almost always AD...and if it is vascular, it still may help.

Vassilis Koliatsos
Frontal miscovascular patients also have amnesia, but it is a frontal type of amnesia.

Steven DeKosky
Yes, but that's a readily identifiable different type of memory loss, isn't it?

Changiz Geula
All, we should also keep in mind that ChE inhibition might work through other mechanisms than cholinergic enhancement. Cholinesterases have a number of other roles and have at the least been implicated in the pathology of AD.

Glenda Bishop
Changiz, what other roles are these?

Steven DeKosky
Changiz, we need the data to show that the clinical effects are detectable....

Changiz Geula
Glenda and Steve, I agree that we need clinical data in terms of disease modification to show if these other roles of cholinesterases are involved. There is primarily data on the possible role of cholinesterases in APP synthesis, Ab production, Ab aggregation and plaque maturation.

Glenda Bishop
It seems that the clinical stages are quite confusing. Wouldn't that mean that there is a chance of treating the patients wrongly, and is there a "safe" medication that could be used in most of these patients?

Steven DeKosky
The esterase inhibitors are quite safe. We just don't want to use any medication if it is not needed or proven to work.

Jim Geddes
Milos and Steve: Were any of the subjects in your study on AChE inhibitors? If so, was there any evidence of an effect on ChAT levels?

Milos Ikonomovic
Jim, they were not on anticholinesterase treatment.

Vassilis Koliatsos
Esterase inhibitors work much more broadly than stimulating the septohippocampal neurons; for example they boost other parts of the diffuse basal forebrain-cortical and limbic projection. I am not sure about effects on plaque formation and maturation.

Changiz Geula
Glenda, cholinergic enhancement may be of cognitive benefit even in normal individuals. Therefore, they will afford some benefit whenever the goal is to enhance cognition.

Glenda Bishop
Changiz, is cholinergic enhancement a good way to improve basic cognitive performance, then? That is, in "normal" people?

Stephen Ginsberg
Glenda, a molecular (or cellular) diagnostic marker is needed, such as a proteomic or genomic profile. The trouble is, we cannot do brain biopsies—maybe cerebrospinal fluid (CSF) or blood may ultimately be useful in this regard.

Vassilis Koliatsos
The basal forebrain cholinergic cortical projection promotes attentional functions. Glenda, look at Voytko et al., 1994.

Changiz Geula
Glenda, the benefits have to be balanced by the side effects and toxicity of higher doses of inhibitors.

Gabrielle Strobel
Steven, there are occasional hints in the press that the esterase inhibitors are being used as cognitive enhancers by people without clear disease. Any thoughts on that?

Steven DeKosky
I believe the data on the use of AChE inhibitors in normal people is understudied. The data are scant, and mostly unblinded. With respect, I think Changiz's comment that they are "of cognitive benefit" is an overstatement.... It is at least premature.

Changiz Geula
Steve, I did preface my statement with "may." There are several studies showing memory enhancement in normals. I agree that more vigorous data is needed.

Glenda Bishop
Steven, can cholinergic function be measured in the CSF at all, or blood for that matter?

Robert Bowser
Steven, better biomarkers are definitely needed to properly diagnose patients. It would appear from the current paper that ChAT activity is a better marker for MCI than tangles.

Milos Ikonomovic
I agree with Bob; you see tangles in both MCI and AD.

Vassilis Koliatsos
Bob, it's like looking for biomarkers for dropsy.

Gabrielle Strobel
Milos and Steve write in the paper that the compensatory response could be used to predict clinical diagnosis. I also wondered how one can measure it in living people?

Elliott Mufson
We have recently found that proNGF is increased in MCI. This may be an early biomarker.

Steven DeKosky
It is another reason that we point to ERC as the culprit in MCI.... AChE inhibitors do not improve memory function much in AD patients; the improvements are predominantly in attention, concentration, etc. That might be expected if the primary reason for the short-term memory loss is the ERC input.

Changiz Geula
Elliot, where did you measure proNGF?

Milos Ikonomovic
Elliott, was that in basal forebrain?

Elliott Mufson
In the parietal cortex!

Robert Bowser
Elliott, how is proNGF identified?

Elliott Mufson
We used a Western blot.

Gabrielle Strobel
Elliott, how specific is this? How much overlap with non-MCI? And is this published?

Glenda Bishop
Eliott, can you detect proNGF in the CSF as well, i.e., in living patients?

Vassilis Koliatsos
Bob, Glenda, Elliot, perforant path lesions increase NGF expression in the hippocampus.

Robert Bowser
Vassilis, correct, and that may be correlating to a sprouting response. But hard to use proNGF as a biomarker.

Vassilis Koliatsos
Agreed, Bob.

Elliott Mufson
We are presenting it at a NS meeting and are writing a paper as we speak!

Vassilis Koliatsos
We have seen it (unpublished). I believe others have published it.

Gabrielle Strobel
Cool. Let us know when it comes out!

Elliott Mufson
I am not sure about CSF, as we have not tried.

Vassilis Koliatsos
NGF may attract and induce sprouting in cholinergic terminals.

Changiz Geula
Elliot, do you think the increase in proNGF may enhance cholinergic sprouting in cortex?

Vassilis Koliatsos
ProNGF usually digests itself to NGF.

Jim Geddes
Vassilis, that was the assumption, but there are now reports that proNGF is the most abundant form in the CNS.

Vassilis Koliatsos
Jim, the active form is still the b not the entire a2/b/g2.

Elliott Mufson
It may, but it also could be related to apoptosis, as proNGF binds with p75NTR.

Steven DeKosky
As you say, the specificity of the proNGF changes needs to be considered.... What about its presence in other neurodegenerative diseases?

Elliott Mufson
The work of Margret Fahnestock has shown that proNGF is increased in end-stage AD as well. We have seen the increase in early AD.

Gabrielle Strobel
Elliott, would this be specific to AD or perhaps indicate a sort of inflammatory state, as NGF turns up in neuroimmunology work quite a bit, in MS, for example?

Elliott Mufson
We are looking at Parkinson's disease (PD). Perhaps we should look at DLB?

Glenda Bishop
Eliott, does that mean that proNGF is increased at all stages of AD?

Elliott Mufson
It appears that proNGF is upregulated in the prodromal stages of AD (MCI) and continues throughout the disease process.

Stephen Ginsberg
Milos and Steve, at the end of the day, do you think upregulation of ChAT will be a useful biomarker for MCI? At the bench postmortem?? In the clinic??

Milos Ikonomovic
Steve, it could be useful, we need a safe way to measure it.

Steven DeKosky
At this moment, I don't think ChAT will be a useful measure; as a clinician—if we are right about the origin of the upregulation, we will want to have something sooner. That is, we will not want to wait until CHAT goes up in response to a degeneration.

Gabrielle Strobel
Elliott, are you looking at BDNF, also?

Vassilis Koliatsos
I believe we need to work more on the models, not on postmortem molecular biology.

Changiz Geula
I have a more general question for Steve, Milos, and Eliot. In light of your study and the earlier one, would you conclude that the cholinergic system in MCI and early AD is functionally normal, or do you entertain the possibility that it is dysfunctional, hence a reactive upregulation and sprouting?

Milos Ikonomovic
Changiz, that's a good point; we don't know how many functional synapses we can find on these sprouting fibers.

Elliott Mufson
In our single-cell gene expression studies, synaptic markers are decreased in MCI.

Steven DeKosky
We have no good evidence that increased ChAT is functional; it is, after all, replacing glutamate inputs in the intermolecular layer. We also keep reminding ourselves that these people were impaired cognitively; we do not have a good way to know whether the ChAT activity was keeping them better. I think we will need some functional marker, not a structural one.

Robert Bowser
Steven, at the moment, though, what is a better marker for MCI?

Gabrielle Strobel Strobel
Steven, how about phospho-tau in CSF, then, as a biomarker?

Vassilis Koliatsos
Gabrielle, I believe the venture to look for markers for MCI is very problematic.

Gabrielle Strobel
Vassilis, why?

Vassilis Koliatsos
Gabrielle, we need all kinds of markers (neurochemical, imaging, neuropsychological) to help us divide MCI up into AD, PD plus, and vascular.

Steven DeKosky
I agree with Vassilis that biomarkers are problematic for MCI at this point. A major problem is that MCI needs to have better and clear criteria or it will be hopelessly confounded in looking at biological markers.

Glenda Bishop
We are now at the end of our hour. Thank you, everyone, for this interesting chat today, and thank you to our authors for the great answers. You are welcome to continue chatting for a while longer.

Gabrielle Strobel
I want to second Glenda: Thanks so much for coming and for such a lively discussion. Please continue on as long as you like. We will follow this area.

 

Background

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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References

News Citations

  1. Revise Mechanism for Alzheimer's Drug? Acetylcholine Increased in Earliest Stage of Disease
  2. AChE Inhibitor Gets Fly Boys' Attention
  3. Can Travel, Will Deposit: Aβ via the Perforant Pathway?

Webinar Citations

  1. Cholinergic Plasticity in Hippocampus of Individuals with Mild Cognitive Impairment: Correlation with Alzheimer's Neuropathology

Paper Citations

  1. . Cholinergic plasticity in hippocampus of individuals with mild cognitive impairment: correlation with Alzheimer's neuropathology. J Alzheimers Dis. 2003 Feb;5(1):39-48. PubMed.
  2. . Differential cholinergic regulation in Alzheimer's patients compared to controls following chronic blockade with scopolamine: a SPECT study. Psychopharmacology (Berl). 1995 Sep;121(2):231-41. PubMed.
  3. . Disruption of corticocortical connections ameliorates amyloid burden in terminal fields in a transgenic model of Abeta amyloidosis. J Neurosci. 2002 Nov 15;22(22):9794-9. PubMed.
  4. . Basal forebrain lesions in monkeys disrupt attention but not learning and memory. J Neurosci. 1994 Jan;14(1):167-86. PubMed.

Other Citations

  1. Glenda Bishop

External Citations

  1. Journal of Alzheimer's Disease

Further Reading

No Available Further Reading