Drug Therapy in Alzheimer's Disease
http://www.100md.com
《新英格兰医药杂志》
To the Editor: In his review article on Alzheimer's disease (July 1 issue),1 Cummings states that there is "increasing consensus" that the production of beta-amyloid (A) peptide is "central to the pathogenesis of Alzheimer's disease." He neglects to mention that there are also data showing that despite massive A accumulation in the brains of animals and humans, there is little associated cell death. Indeed, our work suggests that there is only a weak correlation between A and cognitive decline and that deposition of A is not the earliest neuropathologic event observed in the brains of persons with Alzheimer's disease — numerous A plaques can be found in the brains of elderly people who do not have dementia.2,3 Moreover, A production may play a protective role in the diseased brain4 — a reaction that may explain the temporary appearance of A a few days after a brief episode of traumatic brain injury.5 These and other findings put into doubt the validity of the hypothesis that amyloid is the central cause of Alzheimer's disease and, consequently, the potential usefulness of therapeutic agents that target A.
Jack de la Torre, M.D., Ph.D.
Gjumrakch Aliev, M.D., Ph.D.
George Perry, Ph.D.
Case Western Reserve University
Cleveland, OH 44106
jcdelatorre@cox.net
Dr. Perry reports being a consultant to and owning equity in Voyager Pharmaceuticals.
References
Cummings JL. Alzheimer's disease. N Engl J Med 2004;351:56-67.
Lee HG, Casadesus G, Zhu X, Joseph JA, Perry G, Smith MA. Perspectives on the amyloid-beta cascade hypothesis. J Alzheimer's Dis 2004;6:137-45.
de la Torre JC. Is Alzheimer's disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics. Lancet Neurol 2004;3:184-190.
Plant LD, Boyle JP, Smith IF, Peers C, Pearson HA. The production of amyloid- peptide is a critical requirement for the viability of central neurons. J Neurosci 2003;23:5531-5535.
Gentleman SM, Greenberg BD, Savage MJ, et al. A beta 42 is the predominant form of amyloid beta-protein in the brains of short-term survivors of head injury. Neuroreport 1997;8:1519-1522.
To the Editor: Cummings presents a simple and positive message about cholinesterase inhibitors: "Cholinesterase inhibitors are approved for the treatment of mild-to-moderate Alzheimer's disease and should be considered as a standard of care for patients with Alzheimer's disease." Two references are provided1,2 but these do not reflect the controversy that exists about this class of medication.
The AD2000 trial reported that donepezil was not cost-effective, because the benefits were below minimally relevant thresholds.3 The two references cited by Cummings are actually less positive than as represented in the review article. According to the statement of the American Academy of Neurology, "[cholinesterase inhibitors] should be considered in patients with mild to moderate [Alzheimer's disease] (Standard), although studies suggest a small average degree of benefit."1 The 1997 consensus statement is equally lukewarm.2 Each year, more than a billion dollars are spent on cholinesterase inhibitors, and oversimplification could have unwarranted promotional value in this marketplace.
Thomas E. Finucane, M.D.
Johns Hopkins Bayview Medical Center
Baltimore, MD 21224
tfinucan@jhmi.edu
References
Doody RS, Stevens JC, Beck C, et al. Practice parameter: management of dementia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56:1154-1166.
Small GW, Rabins PV, Barry PP, et al. Diagnosis and treatment of Alzheimer disease and related disorders: consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society. JAMA 1997;278:1363-1371.
Courtney C, Farrell D, Gray R, et al. Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial. Lancet 2004;363:2105-2115.
To the Editor: Cummings highlights some important new developments in the care of patients with Alzheimer's disease. Although posterior parietal hypometabolism is typically found in Alzheimer's disease despite a normal density of benzodiazepine receptors,1 strong caution is warranted in the case of normal-pressure hydrocephalus, in which both clinical changes and changes visible on positron-emission tomography (PET) can normalize with shunting.2 Although in Figure 1 of the article, the PET scan of a patient's brain (Panel B) shows greater posterior parietal hypometabolism on the left than on the right, the magnetic resonance image (Panel A) shows large ventricles that are not typical of Alzheimer's disease and suggests an alternate, reversible possibility not stated by the author: normal-pressure hydrocephalus.
Despite Cummings's discussion of cholinesterase inhibitors, a newly published, long-term, double-blind, placebo-controlled British study failed to show any benefit of cholinesterase inhibitors in Alzheimer's disease.3
Michael A. Meyer, M.D.
Jacobs Neurological Institute
Buffalo, NY 14203
michaelandrewmeyer@yahoo.com
References
Meyer M, Koeppe RA, Frey KA, Foster NL, Kuhl DE. Positron emission tomography measures of benzodiazepine binding in Alzheimer's disease. Arch Neurol 1995;52:314-317.
Schwarzschild M, Rordorf G, Bekken K, Buonanno F, Schmahmann JD. Normal-pressure hydrocephalus with misleading features of irreversible dementias: a case report. J Geriatr Psychiatry Neurol 1997;10:51-54.
Courtney C, Farrell D, Gray R, et al. Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial. Lancet 2004;363:2105-2115.
Dr. Cummings replies: Dr. de la Torre and colleagues cite evidence that the aggregation of A protein may not be the central event in Alzheimer's disease. There are many nonamyloid processes in the brain in Alzheimer's disease, but they do not explain the many pathological, genetic, and molecular observations supporting the primacy of the role of A protein.1 Other pathophysiological events no doubt contribute to the dementia and may also have therapeutic importance.
Dr. Finucane calls attention to two studies that he suggests challenge the wide use of cholinesterase inhibitors. The AD2000 study2 investigating the effect of the use of cholinesterase inhibitors on nursing home placement in the United Kingdom showed a drug–placebo difference after two years in a double-blind, controlled trial and supports the efficacy of cholinesterase inhibitors. The study did not show any difference between the drug and placebo with regard to nursing home placement. Several aspects of the study raise concern. The investigators included atypical patients in cases in which the doctor was "substantially uncertain that the individual would obtain a worthwhile clinical benefit from donepezil." The study was underpowered for many conclusions, with only 566 patients, whereas the estimated necessary sample size was 3000 patients. There was a high rate of attrition in the sample, raising questions about the possible nonrepresentativeness of the remaining patients. There are many influences on nursing home placement, and it is unclear whether factors other than drug–placebo differences were adequately controlled for.
Dr. Finucane also suggests that the guidelines of the American Academy of Neurology3 recommend that cholinesterase inhibitors be "considered" for patients with Alzheimer's disease but do not encourage their use. As cochair of the panel that developed these guidelines, I can clarify that the panel was reluctant to instruct physicians exactly how to prescribe. The word "consider" was used to create the opportunity for clinicians not to prescribe cholinesterase inhibitors in some circumstances — such as cases of hypersensitivity to the drug or when bradycardia was present or in other practice situations that cannot be anticipated in detail in a practice parameter. Nearly all professional organizations that have provided an opinion on the use of cholinesterase inhibitors in practice have recommended their use for appropriate patients; these organizations include the American Academy of Neurology,3 the American Association for Geriatric Psychiatry,4 and the European Federation of Neurological Societies.5
Jeffrey L. Cummings, M.D.
David Geffen School of Medicine at UCLA
Los Angeles, CA 90095-7035
Dr. Cummings reports having been a consultant to Amgen and Wyeth.
References
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002;297:353-356.
Courtney C, Farrell D, Gray R, et al. Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial. Lancet 2004;363:2105-2115.
Doody RS, Stevens JC, Beck C, et al. Practice parameter: management of dementia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56:1154-1166.
Small GW, Rabins PV, Barry PP, et al. Diagnosis and treatment of Alzheimer's disease and related disorders: consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society. JAMA 1997;278:1363-1371.
Waldemar G, Dubois B, Emre M, Scheltens P, Tariska P, Rossor M. Diagnosis and management of Alzheimer's disease and other disorders associated with dementia: the role of neurologists in Europe. Eur J Neurol 2000;7:133-144.
Jack de la Torre, M.D., Ph.D.
Gjumrakch Aliev, M.D., Ph.D.
George Perry, Ph.D.
Case Western Reserve University
Cleveland, OH 44106
jcdelatorre@cox.net
Dr. Perry reports being a consultant to and owning equity in Voyager Pharmaceuticals.
References
Cummings JL. Alzheimer's disease. N Engl J Med 2004;351:56-67.
Lee HG, Casadesus G, Zhu X, Joseph JA, Perry G, Smith MA. Perspectives on the amyloid-beta cascade hypothesis. J Alzheimer's Dis 2004;6:137-45.
de la Torre JC. Is Alzheimer's disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics. Lancet Neurol 2004;3:184-190.
Plant LD, Boyle JP, Smith IF, Peers C, Pearson HA. The production of amyloid- peptide is a critical requirement for the viability of central neurons. J Neurosci 2003;23:5531-5535.
Gentleman SM, Greenberg BD, Savage MJ, et al. A beta 42 is the predominant form of amyloid beta-protein in the brains of short-term survivors of head injury. Neuroreport 1997;8:1519-1522.
To the Editor: Cummings presents a simple and positive message about cholinesterase inhibitors: "Cholinesterase inhibitors are approved for the treatment of mild-to-moderate Alzheimer's disease and should be considered as a standard of care for patients with Alzheimer's disease." Two references are provided1,2 but these do not reflect the controversy that exists about this class of medication.
The AD2000 trial reported that donepezil was not cost-effective, because the benefits were below minimally relevant thresholds.3 The two references cited by Cummings are actually less positive than as represented in the review article. According to the statement of the American Academy of Neurology, "[cholinesterase inhibitors] should be considered in patients with mild to moderate [Alzheimer's disease] (Standard), although studies suggest a small average degree of benefit."1 The 1997 consensus statement is equally lukewarm.2 Each year, more than a billion dollars are spent on cholinesterase inhibitors, and oversimplification could have unwarranted promotional value in this marketplace.
Thomas E. Finucane, M.D.
Johns Hopkins Bayview Medical Center
Baltimore, MD 21224
tfinucan@jhmi.edu
References
Doody RS, Stevens JC, Beck C, et al. Practice parameter: management of dementia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56:1154-1166.
Small GW, Rabins PV, Barry PP, et al. Diagnosis and treatment of Alzheimer disease and related disorders: consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society. JAMA 1997;278:1363-1371.
Courtney C, Farrell D, Gray R, et al. Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial. Lancet 2004;363:2105-2115.
To the Editor: Cummings highlights some important new developments in the care of patients with Alzheimer's disease. Although posterior parietal hypometabolism is typically found in Alzheimer's disease despite a normal density of benzodiazepine receptors,1 strong caution is warranted in the case of normal-pressure hydrocephalus, in which both clinical changes and changes visible on positron-emission tomography (PET) can normalize with shunting.2 Although in Figure 1 of the article, the PET scan of a patient's brain (Panel B) shows greater posterior parietal hypometabolism on the left than on the right, the magnetic resonance image (Panel A) shows large ventricles that are not typical of Alzheimer's disease and suggests an alternate, reversible possibility not stated by the author: normal-pressure hydrocephalus.
Despite Cummings's discussion of cholinesterase inhibitors, a newly published, long-term, double-blind, placebo-controlled British study failed to show any benefit of cholinesterase inhibitors in Alzheimer's disease.3
Michael A. Meyer, M.D.
Jacobs Neurological Institute
Buffalo, NY 14203
michaelandrewmeyer@yahoo.com
References
Meyer M, Koeppe RA, Frey KA, Foster NL, Kuhl DE. Positron emission tomography measures of benzodiazepine binding in Alzheimer's disease. Arch Neurol 1995;52:314-317.
Schwarzschild M, Rordorf G, Bekken K, Buonanno F, Schmahmann JD. Normal-pressure hydrocephalus with misleading features of irreversible dementias: a case report. J Geriatr Psychiatry Neurol 1997;10:51-54.
Courtney C, Farrell D, Gray R, et al. Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial. Lancet 2004;363:2105-2115.
Dr. Cummings replies: Dr. de la Torre and colleagues cite evidence that the aggregation of A protein may not be the central event in Alzheimer's disease. There are many nonamyloid processes in the brain in Alzheimer's disease, but they do not explain the many pathological, genetic, and molecular observations supporting the primacy of the role of A protein.1 Other pathophysiological events no doubt contribute to the dementia and may also have therapeutic importance.
Dr. Finucane calls attention to two studies that he suggests challenge the wide use of cholinesterase inhibitors. The AD2000 study2 investigating the effect of the use of cholinesterase inhibitors on nursing home placement in the United Kingdom showed a drug–placebo difference after two years in a double-blind, controlled trial and supports the efficacy of cholinesterase inhibitors. The study did not show any difference between the drug and placebo with regard to nursing home placement. Several aspects of the study raise concern. The investigators included atypical patients in cases in which the doctor was "substantially uncertain that the individual would obtain a worthwhile clinical benefit from donepezil." The study was underpowered for many conclusions, with only 566 patients, whereas the estimated necessary sample size was 3000 patients. There was a high rate of attrition in the sample, raising questions about the possible nonrepresentativeness of the remaining patients. There are many influences on nursing home placement, and it is unclear whether factors other than drug–placebo differences were adequately controlled for.
Dr. Finucane also suggests that the guidelines of the American Academy of Neurology3 recommend that cholinesterase inhibitors be "considered" for patients with Alzheimer's disease but do not encourage their use. As cochair of the panel that developed these guidelines, I can clarify that the panel was reluctant to instruct physicians exactly how to prescribe. The word "consider" was used to create the opportunity for clinicians not to prescribe cholinesterase inhibitors in some circumstances — such as cases of hypersensitivity to the drug or when bradycardia was present or in other practice situations that cannot be anticipated in detail in a practice parameter. Nearly all professional organizations that have provided an opinion on the use of cholinesterase inhibitors in practice have recommended their use for appropriate patients; these organizations include the American Academy of Neurology,3 the American Association for Geriatric Psychiatry,4 and the European Federation of Neurological Societies.5
Jeffrey L. Cummings, M.D.
David Geffen School of Medicine at UCLA
Los Angeles, CA 90095-7035
Dr. Cummings reports having been a consultant to Amgen and Wyeth.
References
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002;297:353-356.
Courtney C, Farrell D, Gray R, et al. Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial. Lancet 2004;363:2105-2115.
Doody RS, Stevens JC, Beck C, et al. Practice parameter: management of dementia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56:1154-1166.
Small GW, Rabins PV, Barry PP, et al. Diagnosis and treatment of Alzheimer's disease and related disorders: consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society. JAMA 1997;278:1363-1371.
Waldemar G, Dubois B, Emre M, Scheltens P, Tariska P, Rossor M. Diagnosis and management of Alzheimer's disease and other disorders associated with dementia: the role of neurologists in Europe. Eur J Neurol 2000;7:133-144.