Message Board

Olfactory dysfunction, central cholinergic integrity and cognitive impairment in Parkinson?s disease

1. What is acetylcholinesterase and why did they choose to monitor it's activity instead of ACh? What else could they have monitored?

2. In the discussion, the paper cites several studies demonstrating the involvement of the limbic cholinergic system in olfaction and cognition. Please briefly describe one of them and how it relates to the study at hand.

2. Do you think incorporating a "smell test" into the annual health check up would be beneficial? Why or why not? How could they do this?

I thought that the odor test presented in the paper represents an interesting new diagnostic tool in examining Parkinson?s disease, especially since they found some correlation between performance on the test and forebrain cholinergic activity. I?m not sure that an odor test would necessarily be a beneficial test to give to everyone, since it?s not clear what sort of relevance it has to general health, rather, it appears to have some specific utility for those with certain disorders such as Parkinson?s or Alzheimer?s where I think it could indeed prove useful.

Acetylcholinesterase is an enzyme that breaks down the neurotransmitter acetylcholine, and as such, it can be used as an effective measure of acetylcholine activity since there would be more enzymatic activity in correlation with increased acetylcholine release. I remember from Neuro 1 that a number of nerve gases target acetylcholinesterase, and by inhibiting it, basically flood the neuromuscular junction with acetylcholine which causes paralysis. The reason this is effective is because acetylcholinesterase is a very efficient enzyme and very rapidly breaks down acetylcholine; I think that that is the reason the researchers likely did not just use acetylcholine in their PET, since it is degraded extremely quickly and so, could prove difficult to measure especially in comparison to the comparatively long-lived acetylcholinesterase. Aside from that, I think they could have perhaps looked at the acetcylcholine receptors (nicotinic and muscarinic) to give some idea of acetylcholine activity.

I looked at the Larsson, et. al. 2005 article, and from the abstract, it appears that the researchers in that study give a large sample of patients aged from 45 to 90 years an odor test similar to the one described in the other article. The salient result I took from the study was that ?age, sex, education, cognitive speed, and vocabulary? could be correlated with performance on the odor test. The study we are looking at used this study to illustrate that the efficiency of the olfactory system can be correlated with a number of factors, including decreased cognitive faculties, allowing them to use their odor test as a sort of gauge of forebrain cholinergic degradation in Parkinson?s patients.

Acetylecholinesterase (AchE) is the enzyme that breaks down acetylecholine. Like Drew said, I think they tagged AchE because it is not as readily broken down as the neurotransmitter itself. This is especially important in Parkinson patients, where there is already an increase in the production of their Ach, tagging for the neurotransmitter would be messy as well as inaccurate because you can?t really tell how much of it is actually being released. Another enzyme that you can tag is perhaps Choline AcetylTransferase (ChAT). Since it?s an enzyme that produces acetylecholine from acetyl CoA and Choline, there should be an increase in their presence.

I looked at the paper ?Olfactory Impairment Predicts Brain Atrophy in Parkinson's Disease? by Wattendorf et. al. It was a great paper that used MRI to see if there was any correlation between hyposmia and grey matter atrophy. They found positive correlations between olfactory performance and gray matter volume in the right piriform cortex in early PD patients and in the right amygdala in moderately advanced patients. This is the first time that such a correlation was confirmed. It showed that decreased olfaction does indeed play a role in the limbic cortex.

Although decreased sense of smell does not always mean that you are developing Parkinson?s or Alzheimers. I think incorporating a smell test in regular checkups for middle aged to elderly patients could potentially help a lot of people discover their Alzheimer?s or Parkinson?s before the disease advances too far. The UPSIT test isn?t too difficult to administer, a version could be developed for patients to take at home or at the doctor?s office.

As this article clearly demonstrates, limbic function and olfactory performance are correlated. Thus, a simplified version of the smell test may be beneficial in annual health exams, which currently are lacking uncomplicated methods measuring limbic function. However, this particular article only pertained to Parkinson?s patients, and we (to the extent of my knowledge) do not yet know whether the severity of other limbic and cognitive disorders are directly related to olfaction. If Parkinson?s and Alzheimer?s disease are the only disorders known to demonstrate this correlation, perhaps ?smell tests? should only be administered to patients of high risk, older patients with a close relative with the disease.

Carballo-Marquez et al. conducted a study on the extent of cholinergic control in the limbic system similar to this one, which Bohnen et al. cited (Muscarinic Receptor Blockade in Ventral Hippocampus and Prelimbic Cortex Impairs Memory for Socially Transmitted Food Preference, 2008). Within this study, adult rats were bilaterally injected with scopolamine, a muscarinic antagonist, into their ventral hippocampus or prelimbic cortex, resulting in limited acetylcholine activity in these areas. Prelimbic cortex injections resulted in the complete abolition of recently acquired memories, in this case the rat?s social acclimation towards a food preference. Ventral hippocampal injections reduced the rats? trained behavior, but their performance was still higher than that of the prelimbic cortex test group, better than chance alone would dictate their performance to be. The rats? decreased ability to form and process memory easily relates back to the decrease in cognitive processing seen in Parkinson?s patients, both stemming from limbic cholergic dysfunction. Clearly, the limbic cholergic system is essential for social, higher-order memory formation, and cognition.

(PS I feel as though Nick and Drew have done an excellent job explaining AChE already as an enzyme responsible for the degradation of acetylcholine. I feel their explanation leaves little to be improved upon. However, I suppose the precursors of Ach themselves, acetyl CoA and Choline could also be monitored as a means of quantifying Ach.)

Acetylcholinesterase (AChE) is the enzyme that breaks down acetylcholine (Ach) in the synaptic cleft to keep it from continuously stimulating the post-synaptic membrane. It is possible the researchers chose to monitor its activity rather than that of ACh itself because the levels of ACh were too small to be measured accurately (seeing as we?re talking about part of one of the diffuse modulatory systems of the brain and not much neurotransmitter is needed to evoke a post-synaptic response) or because it is simply easier to track the activity of the enzyme that breaks down ACh because it exists for longer periods of time. Increased AChE activity would signal increased amounts of Ach and vice versa, providing a somewhat more simple method of tracking the activity of ACh in the synaptic cleft. Drew and Nick have really covered it well already, and Caley's point on the precursors to ACh is an interesting one as far as measuring ACh goes.

Incorporating a ?smell test? into annual health check-ups could be beneficial in the early detection of dementia (since dementia, according to this study, appears to be linked somewhat to loss of olfactory faculties). As stated in the study, patients with a Hoehn and Yahr score of 2 or below ?demonstrated significant correlation between striatal VMAT2 activity and UPSIT,? and patients with a score of 2.5 or higher ?demonstrated a borderline trend between striatal VMAT2 acitivity and UPSIT scores.? This shows that Parkinson?s patients, both in the early and late stages, showed decreased olfactory abilities, which could make a ?smell test? useful clinically for detection of Parkinson?s at any point. It could also be used, as stated earlier, to detect dementia to a certain extent, which could also be highly informative and useful in the hospital setting. It must be kept in mind, though, that hyposmia is not necessarily indicative of a neurodegenerative disorder: the patient could very well just have a cold.

To expand upon the topic at hand, I read the De Rosa article on how the basal forebrain nuclei innervated with cholinergic neurons help to proactively interfere with stored odor memory in rats. These rats' basal forebrain nuclei around the "horizontal limb of the diagonal band of Broca," as well as all of the basal forebrain nuclei in some rate, were lesioned using 192 IgG-saporin, an immunotoxin that selectively destroys cholinergic basal forebrain neurons. These rats had no problems in the given "olfactory discrimination task." After being injected with scopolamine (an anticholinergic), however, the rats with lesions in all of their basal forebrain nuclei demonstrated an increased susceptibility to proactive interference. This led the scientists to conclude that weakened cholinergic modulation in lesioned BF nuclei can lead to proactive interference such as that seen in the study when the remaining ACh in the system is removed. This relates to the study we originally read in that it shows how diminished ACh input dramatically affects olfaction, which can then be linked to Parkinson's disease because of the similar degradation of cholinergic neurons in that disease process.

I don't know if it is necessary to state what AchE is since everyone else already has, but I suppose I shall anyway. Acetylcholinesterase is an enzyme that breaks down acetylcholine! I agree with Caley that since Ach is made up of Acetyl coA and choline, it may be possible to measure amounts of these as well. This could only be possible if there was enough of each substance to be accurately measured.

To expand upon Nick's points about the Olfactory Impairment Predicts Brain Atrophy in Parkinson's Disease by Wattendorf et. al., I would like to go more into how they tested the effectivity of the sense of smell and how this could be done easily in doctors offices to answer your last question. In this experiment, after they tested the functions of the brain via MRI, they tested olfaction. To do this it states they used a simple "Sniffin' Sticks" test. To assess the correctness of "smell" they were measured then on their nonverbal odor threshold (T), their nonverbal discrimination (D), and their verbal identification (I). These would then be combined to get the final score of olfaction. Now as Nick said before, this experiment demonstrated that decreased olfaction did effect the limbic cortex.

It would appear that the experiment performed above to test olfaction could be performed in a doctor's office as well. Though I don't feel it to be necessary to do this in a annual checkup, it may be a test that could be performed when you are over the age of 55, where symptoms for Parkinson's would begin to appear. Since there is no real cure for Parkinson's I'm not sure how much of a difference it would be to know that you have a higher chance of getting it, though people are always wanting to prepare. If "Sniffin' Sticks" are available at a reasonable price then it could be used in checkups and make it possible for general testing to occur.

Well, as above, AChE is a degradation enzyme that breaks ACh into it base chemicals, acetyl CoA and Choline. AChE functions to reduce the amount of ACh in the synaptic cleft so that continuous stimulation does not occur. The important parts of why they chose this chemical have already beens tated as well (the brief presence of ACh and the extended presence of the enzyme that breaks it down). And of course, using the precursors to this NT would be effective in tracking cholinergic function as they exist in the synapse after AChE breaks ACh down.

The smell test could be incorporated as an additive measure to diagnosing Parkinson's or Alzheimer's disease. However, I think its best function would be as a supplemental test to assessing the severity of the disease. It could also fast track diagnosis. However, decreased Olfaction alone is not representative of Parkinson's and/or Alzheimer's. As Caley stated, The UPSIT test does not seem to be too complicated and could be simplified further to be used as a quick out patient test or even a take home test; though, as a test for the severity of a disease, I would imaging that is not news that one would want to discover at home.

I looked further into the Hunter Murray journal. The test they ran was on rats. They habituated odor memory and then administered chemical cholinergic antagonists or began with antagonists. The antagonist inhibited habituation after administrations (learning occurred and memory was formed for scents giving before the administration of the antagonists, however anything after elicited a severely decreased response). The antagonists used were N-methylscopolamine and scopolamine, the chemical produced from nightshade plants. The conclusion is that the blockage of cholinergic neurons impared the learning ability of the rats. This is relevant to the paper as the focus is on the lack of cholinergic neurons and the observation their of by the effects on olfaction. Thus, the inability to recognize odors, by retaining a memory of it, can be related to the lack of cholinergic neurons.

Like other people have said, AChE is an enzyme that breaks down the neurotransmitter acetylcholione. AChE is a better tool for measurement because it is not as readily broken down as acetylcholine. Since we already knew that levels of acetylcholine where higher in people with Parkinson?s and Alzheimer's, assessing the levels of AChE is beneficial in our understanding of why these levels are higher and if this is a result of inactive AChE. As we see, AChE levels increase with increased acetylcholine levels and therefore cannot be the cause of increased acetylcholine levels, just correlative.

As for incorporating a smell test into the annual checkup, I think much more research needs to be done to address the relationship between lack of smell and the two neuro-degenerative disorders. If it where to be implemented, the smell ability would have to be incorporated to some sort of baseline measurement and compared to previous performance. This comparison would allow individualized smell ability to be addressed and possibly rule out variations across populations. On top of this, it would be necessary to implement a review of cognitive function to address this issue as well. I think that the main difficulty with the smell test is the variable functionality of our noses based on our health and recent olfactory desensitization. Like clementine said, they could just have a cold. However, if it could work there is no reason not to.

I read the paper Mapping of brain acetylcholinesterase alterations in Lewy body disease
by PET. This paper compared the AChE activity of patients with both early and late stage Parkinsons?s. It showed that cholinergic dysfunction occurs early in the cerebral cortex, especially the medial occipital cortex. The dysfunction then becomes more widespread as the disease progresses. This is important because the paper showed alterations in acetylcholine despite cognitive symptoms and early in disease progression. This seems to be the stage just prior to most patients in this study, who showed both cognitive and acetylcholine dysfunction without dementia. These two articles can provide insight into the progression of cognitive defects assossciated with AChE activity and Parkinson?s.