Do cholinesterase inhibitors modify disease progression

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Abstract: Much evidence shows that cholinesterase inhibitor drugs such as Aricept, Exelon and reminyl are clinically effective treatments for people with Alzheimer's disease, and probably also help people with other dementias such as dementia with Lewy bodies (DLB) and dementia developing as a complication of Parkinson's disease. It is important to find out whether these drugs also slow down the changes that occur in the brain. Unfortunately, most of the clinical trials of cholinesterase inhibitor drugs are too short (usually six months) to answer this question. Recent work has made progress in addressing this issue by showing that cholinesterase inhibitors may reduce the deposits of amyloid, the protein at the core of the plaques that develop in the brain of people with Alzheimer's disease. Clinical studies looking at amyloid in the blood, the spinal fluid and brains donated to research by people with Alzheimer's disease after their deaths show reductions in amyloid deposits of up to 70 per cent in people treated with cholinesterase inhibitors. These clinical studies are supported by several other strong pieces of evidence from experimental studies which show that cholinesterase inhibitors and other similar therapies reduce the accumulation of amyloid in nerve cells grown in the laboratory and in specially bred mice that develop amyloid plaques.

There are also several other ways in which cholinesterase inhibitor drugs may help protect the brain. For example, early studies looking at animals and brains donated by people with dementia suggest that helping to maintain the function of the cholinergic nerves, the main treatment goal of the cholinesterase inhibitor drugs, may be important in sustaining the stem cells that are present in the adult brain. We do not yet understand what these stem cells do in the adult brain, but it has been suggested that they may help repair some of the damage that occurs after stroke in people with dementia. In addition, acetylcholinesterase (the chemical messenger that is the main treatment target of cholinesterase inhibitors) has a number of different sub-types. One of these, called the R variant, is increased when nerve cells are damaged and may help protect nerve cells from further damage.

Different individual cholinesterase inhibitor drugs may also have additional beneficial properties. Reminyl, for example, also acts at nicotine receptors on nerve cells. Although it has not been determined whether this action of Reminyl gives any specific benefits, there is certainly evidence from clinical and animal studies showing that nicotine itself does protect nerve cells and may reduce the accumulation of amyloid deposits in the brain. Another cholinesterase inhibitor drug, Exelon, inhibits another cholinesterase chemical messenger (called butyrylcholinesterase) which appears to contribute to the symptomatic benefits from treatment. There is also some emerging evidence that natural variations in butyrylcholineserase levels are related to the rate of disease progression in Alzheimer's disease and dementia with Lewy bodies, but we do not yet know whether the actions of Exelon on butyrylcholinesterase inhibitor have any direct impact on the progression of Alzheimer's disease in the brain.

If it is confirmed that cholinesterase inhibitors slow down the progression of key disease changes in the brain, it is likely that the ongoing benefits of long term treatment have been underestimated, with important implications for the way in which these drugs should be prescribed to give maximum benefit to people with Alzheimer's disease.


The Journal of Quality Research in Dementia, Issue 2 (lay summary)

Do cholinesterase inhibitors modify disease progression in Alzheimer's disease: emerging scientific evidence

Clive Ballard

Director of Research, Alzheimer's Society and Professor of Age Related Diseases, The Wolfson CARD, The Wolfson Wing, Hodgkin Building, Guy's Campus, London SE1 1UL; Telephone 020 7848 8054; Fax 020 7848 6145; Email clive.ballard@kcl.ac.uk


Background

A substantial evidence base clearly demonstrates that cholinesterase inhibitors are a clinically effective treatment for people with Alzheimer's disease,1,2,3 with emerging working suggesting benefits for people with other dementias such as dementia with Lewy bodies (DLB) and Parkinson's disease dementia,4,5 which between them account for 70 per cent of the millions of people with dementia worldwide.6

A key question is whether cholinesterase inhibitors do more than just improve symptoms and also impact upon the disease process in people with these dementias. The long term treatment effects of cholinesterase inhibitors are difficult to interpret from existing studies. The duration of double blind assessment (usually six months) is inadequate to examine any potential disease modifying impact. Although reports of longer term treatment over a number of years have suggested sustained stabilisation in a substantial proportion of people,7 these studies are not placebo-controlled and therefore prone to a variety of biases.

Recent work has, however, taken this debate forward, indicating that cholinesterase inhibitors may impact upon the deposition of β-amyloid (Aβ) in the brain. Aβ is one of the core pathological substrates of Alzheimer's disease. It is seen as diffuse deposits throughout the brain and at the core of the senile plaques that are one of the hallmarks of the disease and therefore represents a key treatment target. There are several strong pieces of evidence from experimental studies showing that cholinesterase inhibitors and other cholinergic therapies reduce the accumulation of amyloid in cultured neurones and in rodent models (Figure 1).8,9,10

Figure 1 Nicotine reduces Aβ in Transgenic mice.

More recently there is exciting new evidence from small clinical trials utilising CSF biomarkers supporting the conclusions of the experimental work. For example, A• concentrations in cerebrospinal fluid from patients were reduced two-fold after administration of the muscarinic M1 receptor agonist talsaclidine for four weeks in a double blind placebo-controlled trial of 40 patients.11 In a further pilot clinical study comparing 27 cholinesterase inhibitor-treated AD patients with matched untreated patients for one year, increases in CSF A• were prevented by both rivatigamine and tacrine treatment.12 In a recent study examining the impact of anticholinergic treatments upon amyloid pathology, there was a significant 2.5 fold increase in amyloid plaque densities in people with Parkinson's disease treated with these agents.13 This study supports the hypothesis that cholinergic therapies may impact upon A•, and, more importantly, highlights that an autopsy approach is a viable method for examining key differences in amyloid pathology related to treatment effects. In the first human autopsy study examining the impact of cholinesterase inhibitor therapy upon amyloid pathology in the brain, we compared 15 DLB patients treated with cholinesterase inhibitors as part of placebo-controlled trials with 15 matched untreated patients, demonstrating that DLB patients treated with cholinesterase inhibitors had 68 per cent less parenchymal A• deposition in the cerebral cortex than untreated patients, an impact similar to that of the Alzheimer vaccine. Consistent with these data, a recent clinical trial demonstrated a reduction in the progression of hippocampal atrophy on MRI in cholinesterase inhibitor-treated patients.14

Although the impact of cholinesterase inhibitors upon A• deposition has been the most widely studied potential influence of treatment upon mechanisms underlying disease progression, there are also several other lines of research emphasising potential neuroprotective properties of the cholinergic system. For example, animal studies15 and recent work examining donated autopsy tissue indicate an association between reduced cholinergic innervation and a reduction in endogenous neural stem cells in the brain.16 Although speculative at the moment, it has been hypothesised that these endogenous stem cells may play an important role in repairing brain damage related to Alzheimer's disease17 and stroke,18 with groundbreaking studies demonstrating an increase of stem cell activity in people with Alzheimer's disease and after a stroke (Minger et al, 2005).19 It is therefore a key question for further research that cholinesterase inhibitors may enhance brain repair.

Acetylcholinesterase, the enzyme that is the main treatment target of cholinesterase inhibitors, has a number of variations including different isomers and sub-types with different molecular weights comprised of different combinations of constituent G protein sub-units, with or without membrane anchoring proteins. In the main, these subtle variations do not make a major difference to the role of acetylcholinesterase or its effectiveness in breaking down acetylcholine in the cholinergic neuronal synapses. However, important studies have demonstrated that there is an increase of the R isomer of acetylcholine in response to cell stress.20 This form is more soluble than the main synaptic subtype, and appears to be neuroprotective and increase stem cell activity20 in animal studies. In people with Alzheimer's disease, an increase in the R isomer appears to be associated with a slower illness progression.20 This is of particular relevance to treatment with cholinesterase inhibitors as most agents in this class also increase the release of the R isomer. Although further research is needed to clarify the importance of the R isomer as a treatment target, this again highlights the potential disease modifying properties of cholinesterase inhibitors.

Different agents within the cholinesterase inhibitor class may also have additional beneficial properties. Galanthamine for example also acts as an allosteric modulator at α-7 nicotinic receptors. It has not been determined whether this action of galanthamine confers any specific neuroprotective properties. However, there is certainly a body of evidence from clinical and animal studies indicating that nicotine itself has neuroprotective properties, and that administration of nicotine may alter the processing of A• and related proteins21, 8 and reduce the deposition of A• and related proteins in the brain. Another cholinesterase inhibitor, rivastigmine, inhibits a different cholinesterase enzyme (butyrylcholinesterase) as well as acetylcholinesterase, which appears to contribute to the symptomatic benefits.12 There is also some emerging evidence that butyrylcholineserase activity is related to the rate of disease progression in Alzheimer's disease,22,23,24 but it has not yet been established whether the butyrylcholinesterase inhibitor actions of rivastigmine have any direct impact on the progression of disease pathology.

Conclusion

There is important emerging evidence which strongly indicates that cholinesterase inhibitors have a range of beneficial impacts on mechanisms which influence the development of core disease pathology in AD. Further research to clarify the mechanisms of action and their impact will be essential to inform the optimal use of these agents. Most importantly, if it is confirmed that cholinesterase inhibitors slow down the progression of key disease pathologies, it is likely that the ongoing benefits of long term treatment have been underestimated, with important implications for the way in which these agents should be prescribed to give optimal benefit to people with Alzheimer's disease.

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