- Email: [email protected]
Donepezil for severe Alzheimer's disease
Correspondence
Bengt Winblad and co-workers (April 1, p 1057)1 conclude that donepezil improves cognition and preserves function in nursing home patients with severe Alzheimer’s disease. Some points should be discussed before accepting this conclusion. Although Winblad and colleagues mention that a CT or MRI scan consistent with Alzheimer’s disease was required for entry into the study, such imaging is insufficient to distinguish Alzheimer’s disease from other types of dementia, especially vascular dementia resulting from cerebral ischaemia. It has been reported that applied fluorodeoxyglucose positron emission tomography accurately separates vascular dementia from Alzheimer’s disease.2 Additionally, abnormal levels of β-amyloid, tau, and a phosphorylated version of tau in cerebrospinal fluid can distinguish Alzheimer’s disease from other types of dementia.3 Since donepezil is ineffective in dementias other than Alzheimer’s disease, the precise diagnosis is essential. Winblad and colleagues report that eligible patients in both groups took concomitant drugs for rheumatic diseases. They did not mention the proportion of eligible patients taking non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs protect against Alzheimer’s disease and its progression by suppressing chronic inflammation and reducing β-amyloid formation in the brain.4 Winblad and co-workers need to show that use of NSAIDs did not affect their conclusion. We declare that we have no conflict of interest.
Yujiro Kida, *Tetsuji Sato [email protected] Department of Anatomy II, Tsurumi University, School of Dental Medicine, 2-1-3 Tsurumi, Tsurumi-Ku, Yokohama, 230-8501, Japan (YK, TS); and Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan (YK) 1
Winblad B, Kilander L, Eriksson S, et al. Donepezil in patients with severe Alzheimer’s disease. Lancet 2006; 367: 1057–65.
www.thelancet.com Vol 368 July 29, 2006
2
3
4
Kerrouche N, Herholz K, Mielke R, et al. (18)FDG PET in vascular dementia: differentiation from Alzheimer’s disease using voxel-based multivariate analysis. J Cereb Blood Flow Metab 2006; published online March 8. DOI: 10.1038/sj.jcbtm.9600296. Ruetschi U, Zetterberg H, Podust VN, et al. Identification of CSF biomarkers for frontotemporal dementia using SELDI-TOF. Exp Neurol 2005; 196: 273–81. Townsend KP, Pratico D. Novel therapeutic opportunities for Alzheimer’s disease: focus on nonsteroidal anti-inflammatory drugs. FASEB J 2005; 19: 1592–601.
We feel that the paper by Bengt Winblad and colleagues1 on the use of donepezil for patients with severe Alzheimer’s disease omits two essential points which should be considered when interpreting this study. The first point is that there is now increasing evidence that donepezil has more than one mechanism of action. As well as being an acetylcholinesterase inhibitor, there is mounting support for the idea that donepezil, and also galantamine, have additional neuroprotective activity. Clinical studies2,3 have shown that use of these drugs at an early stage results in delayed progression of the disease, and increased longevity, implying a diseasemodifying effect rather than the simple suppression of symptoms that might be expected from acetylcholinesterase inhibition. Basic research4 suggests that this neuroprotective effect is due to the ability of these drugs to inhibit the aggregation and toxicity of the β-amyloid peptide that accumulates within senile plaques. The second point is related to the first in that donepezil is most effective in delaying disease progression in patients with the apolipoprotein E ε4 genotype,5 who have very high levels of senile plaque formation. We welcome this study and strongly agree with Winblad and colleagues’ view that donepezil is of benefit to these patients. In our experience, even small improvements make a real difference to the quality of life of patients and carers. We declare that we have no conflict of interest.
David Allsop, Francis L Martin, Susan Moore, *Nigel J Fullwood, on behalf of the Alzheimer’s Society
[email protected] Biomedical Sciences Unit, Lancaster University, Lancaster LA1 4YQ, UK 1
2
3
4
5
Winblad B, Kilander L, Erikkson S, et al. Donepezil in patients with severe Alzheimer’s disease: double-blind, parallel-group, placebocontrolled study. Lancet 2006; 367: 1057–65. Hashimoto M, Kazui H, Matsumoto K, Nakano Y, Yasuda M, Mori E. Does donepezil treatment slow the progression of hippocampal atrophy in patients with Alzheimer’s disease? Am J Psychiatry 2005; 162: 676–82. Raskind MA, Peskind ER, Truyen L, Kershaw P, Damaraju CV. The cognitive benefits of galantamine are sustained for at least 36 months: a long-term extension trial. Arch Neurol 2004; 61: 252–56. Kimura M, Komatsu H, Ogura H, Sawada K. Comparison of donepezil and memantine for protective effect against amyloid-beta(1-42) toxicity in rat septal neurons. Neurosci Lett 2005; 391: 17–21. Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005; 352: 2379–88.
Treatment with cholinesterase inhibitors such as donepezil is increasingly important for cardiologists because patients are living longer and are thus more likely to develop Alzheimer’s disease. The listed cardiac side-effects of donepezil include bradycardia and atrioventricular heart block. Bengt Winblad and colleagues1 found that donepezil improved cognition in patients with severe Alzheimer’s disease, but the data were only reported for 6 months of treatment. In another study on younger patients with mild cognitive impairment,2 donepezil improved cognition for 12 months, with a hazard ratio of 0·42 (95% CI 0·24–0·76; n=253) but by 36 months there was no significant benefit. Is there a difference between these results such that if Winblad and colleagues’ study were continued for longer, the apparent early benefit would fade? Or is there a true difference in the pattern of benefit of donepezil between mild cognitive loss in those with mean age 73 years and those about 11 years older with severe Alzheimer’s disease? The latter seems the less likely of the two possibilities, because mild cognitive loss is a recognised risk factor for full-blown Alzheimer’s disease.3 To distinguish
We do not have the rights to reproduce this image on the web.
e-mail submissions to [email protected]
361
Science Photo Library
Donepezil for severe Alzheimer’s disease
Bengt Winblad and co-workers (April 1, p 1057)1 conclude that donepezil improves cognition and preserves function in nursing home patients with severe Alzheimer’s disease. Some points should be discussed before accepting this conclusion. Although Winblad and colleagues mention that a CT or MRI scan consistent with Alzheimer’s disease was required for entry into the study, such imaging is insufficient to distinguish Alzheimer’s disease from other types of dementia, especially vascular dementia resulting from cerebral ischaemia. It has been reported that applied fluorodeoxyglucose positron emission tomography accurately separates vascular dementia from Alzheimer’s disease.2 Additionally, abnormal levels of β-amyloid, tau, and a phosphorylated version of tau in cerebrospinal fluid can distinguish Alzheimer’s disease from other types of dementia.3 Since donepezil is ineffective in dementias other than Alzheimer’s disease, the precise diagnosis is essential. Winblad and colleagues report that eligible patients in both groups took concomitant drugs for rheumatic diseases. They did not mention the proportion of eligible patients taking non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs protect against Alzheimer’s disease and its progression by suppressing chronic inflammation and reducing β-amyloid formation in the brain.4 Winblad and co-workers need to show that use of NSAIDs did not affect their conclusion. We declare that we have no conflict of interest.
Yujiro Kida, *Tetsuji Sato [email protected] Department of Anatomy II, Tsurumi University, School of Dental Medicine, 2-1-3 Tsurumi, Tsurumi-Ku, Yokohama, 230-8501, Japan (YK, TS); and Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan (YK) 1
Winblad B, Kilander L, Eriksson S, et al. Donepezil in patients with severe Alzheimer’s disease. Lancet 2006; 367: 1057–65.
www.thelancet.com Vol 368 July 29, 2006
2
3
4
Kerrouche N, Herholz K, Mielke R, et al. (18)FDG PET in vascular dementia: differentiation from Alzheimer’s disease using voxel-based multivariate analysis. J Cereb Blood Flow Metab 2006; published online March 8. DOI: 10.1038/sj.jcbtm.9600296. Ruetschi U, Zetterberg H, Podust VN, et al. Identification of CSF biomarkers for frontotemporal dementia using SELDI-TOF. Exp Neurol 2005; 196: 273–81. Townsend KP, Pratico D. Novel therapeutic opportunities for Alzheimer’s disease: focus on nonsteroidal anti-inflammatory drugs. FASEB J 2005; 19: 1592–601.
We feel that the paper by Bengt Winblad and colleagues1 on the use of donepezil for patients with severe Alzheimer’s disease omits two essential points which should be considered when interpreting this study. The first point is that there is now increasing evidence that donepezil has more than one mechanism of action. As well as being an acetylcholinesterase inhibitor, there is mounting support for the idea that donepezil, and also galantamine, have additional neuroprotective activity. Clinical studies2,3 have shown that use of these drugs at an early stage results in delayed progression of the disease, and increased longevity, implying a diseasemodifying effect rather than the simple suppression of symptoms that might be expected from acetylcholinesterase inhibition. Basic research4 suggests that this neuroprotective effect is due to the ability of these drugs to inhibit the aggregation and toxicity of the β-amyloid peptide that accumulates within senile plaques. The second point is related to the first in that donepezil is most effective in delaying disease progression in patients with the apolipoprotein E ε4 genotype,5 who have very high levels of senile plaque formation. We welcome this study and strongly agree with Winblad and colleagues’ view that donepezil is of benefit to these patients. In our experience, even small improvements make a real difference to the quality of life of patients and carers. We declare that we have no conflict of interest.
David Allsop, Francis L Martin, Susan Moore, *Nigel J Fullwood, on behalf of the Alzheimer’s Society
[email protected] Biomedical Sciences Unit, Lancaster University, Lancaster LA1 4YQ, UK 1
2
3
4
5
Winblad B, Kilander L, Erikkson S, et al. Donepezil in patients with severe Alzheimer’s disease: double-blind, parallel-group, placebocontrolled study. Lancet 2006; 367: 1057–65. Hashimoto M, Kazui H, Matsumoto K, Nakano Y, Yasuda M, Mori E. Does donepezil treatment slow the progression of hippocampal atrophy in patients with Alzheimer’s disease? Am J Psychiatry 2005; 162: 676–82. Raskind MA, Peskind ER, Truyen L, Kershaw P, Damaraju CV. The cognitive benefits of galantamine are sustained for at least 36 months: a long-term extension trial. Arch Neurol 2004; 61: 252–56. Kimura M, Komatsu H, Ogura H, Sawada K. Comparison of donepezil and memantine for protective effect against amyloid-beta(1-42) toxicity in rat septal neurons. Neurosci Lett 2005; 391: 17–21. Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005; 352: 2379–88.
Treatment with cholinesterase inhibitors such as donepezil is increasingly important for cardiologists because patients are living longer and are thus more likely to develop Alzheimer’s disease. The listed cardiac side-effects of donepezil include bradycardia and atrioventricular heart block. Bengt Winblad and colleagues1 found that donepezil improved cognition in patients with severe Alzheimer’s disease, but the data were only reported for 6 months of treatment. In another study on younger patients with mild cognitive impairment,2 donepezil improved cognition for 12 months, with a hazard ratio of 0·42 (95% CI 0·24–0·76; n=253) but by 36 months there was no significant benefit. Is there a difference between these results such that if Winblad and colleagues’ study were continued for longer, the apparent early benefit would fade? Or is there a true difference in the pattern of benefit of donepezil between mild cognitive loss in those with mean age 73 years and those about 11 years older with severe Alzheimer’s disease? The latter seems the less likely of the two possibilities, because mild cognitive loss is a recognised risk factor for full-blown Alzheimer’s disease.3 To distinguish
We do not have the rights to reproduce this image on the web.
e-mail submissions to [email protected]
361
Science Photo Library
Donepezil for severe Alzheimer’s disease