One recent survey found that more than 1 in 4 patients who have mild cognitive impairment (MCI) were receiving cholinesterase inhibitors in Italian AD treatment centers even though these medications were being used "off-label."
Memory complaints are ubiquitous in our aging population. Vexing as it can be to misplace one's keys temporarily or to forget the motivation for a trip to the basement, a more fundamental fear of many older adults is that today's forgetfulness will usher in tomorrow's dementia. In some settings, medications indicated for treatment of mild to severe Alzheimer disease (AD) are offered to persons with more subtle cognitive lapses.
One recent survey found that more than 1 in 4 patients who have mild cognitive impairment (MCI) were receiving cholinesterase inhibitors in Italian AD treatment centers even though these medications were being used "off-label."1 In the United States, the FDA has not approved any medication for use in treating MCI. Should we consider this syndrome amenable to pharmacotherapy? What is the evidence that medications might relieve present symptoms or reduce future decline? What are the potential harms associated with such treatment? The following composite and anonymized vignette addresses some of the issues that are increasingly brought to physicians who prescribe neuropsychiatric medications.
Case VignetteMrs Keyes, a youthful 72-year-old piano teacher, has been urged by her concerned children to have a memory evaluation. She continues to give music lessons, manage her household, and perform activities of daily living with no major difficulty. During the past 2 years, however, she has noted greater difficulty in recalling the names of acquaintances and learning new names. On one occasion, she attended a friend's birthday party but several weeks later could not recall having done so. She has more trouble finding an unfamiliar location than previously. She takes longer to balance her checkbook, although she still does it correctly. At times, she has felt "blue" for more than a few days in a row, and she has wondered whether she is depressed.
Her medical history is notable for hypertension, appropriately medicated, but otherwise she appears to enjoy good health. Laboratory studies (complete blood cell count, metabolic panel, fasting lipid profile, and levels of thyroid-stimulating hormone, B12, folate, and homocysteine) show no abnormalities. Ultrasound studies show no significant carotid stenosis or plaque formation. MRI shows mild periventricular white matter disease. Neuropsychological testing results do not support a diagnosis of dementia, but her score on a test of delayed recall is significantly lower than would be expected for her age and educational level. Her executive dysfunction is clinically insignificant. She and her family ask what the future holds for her and whether medication might improve her memory or her prognosis.
Mrs Keyes' forgetfulness, preserved activities of daily living, demonstrable impairment of delayed recall, and lack of dementia are consistent with a diagnosis of MCI.2 Subtyping of MCI, which may have etiologic and prognostic significance, is based on identification of the affected cognitive areas and whether one or more have declined. Mrs Keyes' syndrome of impaired delayed recall with little executive dysfunction would be classified as amnestic, single-domain MCI.3
MCI and AD
When Mrs Keyes and her children investigate MCI in the library and on the Internet, their concern may have been heightened by learning that amnestic MCI is considered a possible precursor to AD. This link is based on the compelling epidemiological evidence that persons with amnestic MCI convert to AD at an accelerated rate compared with the general elderly population.4 Furthermore, the connection between amnestic MCI and AD is bolstered by findings in patients with amnestic MCI of increased hippocampal atrophy,5 specific abnormal positron emission tomography scan findings,6 and AD-like neuropathological changes on autopsy.7 A recently published study indicated that even the minimal deficit that is termed "very mild cognitive impairment" is associated with an increased rate of conversion to AD, and this finding is sure to fan the flames of public and clinical anxiety about the prognostic implications of "senior moments."8
On the basis of this accumulating data, MCI has increasingly seized public and professional interest. We are still at the beginning of sorting out the implications of an MCI diagnosis, however, and there is no standardized approach to treatment. Vascular risk factors and deleterious effects of medications and substances should be controlled. Some evidence supports the value of a healthful diet and appropriate levels of physical exercise9 and of cognitive rehabilitation.10 Pharmacotherapy for patients with MCI, although common in some settings, is undertaken on the basis of limited data that offer minimal encouragement. To answer the Keyes' question about pharmacotherapy, let's review what we can learn from available studies.
MCI has been treated "by analogy" based on interventions designed for patients with AD or other dementias. Medications that have some efficacy in treating AD's cognitive impairments, in particular, have been explored. The most impressive study of a cholinesterase inhibitor in patients with MCI is that of Petersen and colleagues,11 who compared the effects of vitamin E (2000 IU/d) or donepezil (Aricept; target dosage of 10 mg/d) with placebo in patients with amnestic MCI over a 3-year double-blind trial.
The primary outcome measure, conversion to AD, was diminished during the initial 12 months of this study. Converter rates are not specifically reported, but a visual inspection of the study's Figure 1 suggests that the number needed to treat associated with prevention of conversion at 12 months must be greater than 10, which means that at least 10 patients would need donepezil treatment for one to achieve a benefit unexplainable by placebo effect. By the end of 3 years, conversion rates were similar for donepezil, vitamin E, and placebo except for a reduced rate of conversion among the donepezil-treated group of patients with MCI who carried 1 or 2 apolipoprotein E (ApoE) e4 alleles. The result of this secondary analysis has been attributed to the greater statistical power conferred by the higher rate of conversion to AD among ApoE e4 patients and has not been generally suggested to justify routine testing for ApoE genotype or routine prescribing of donepezil for ApoE e4-positive persons with MCI. Furthermore, 36% of patients who are treated with donepezil discontinued the medication because of adverse effects that included GI symptoms, muscle cramps, insomnia, and abnormal dreams.
Enthusiasm for treating MCI with cholinesterase inhibitors has received no stronger support from several other published trials. An earlier placebo-controlled donepezil trial in MCI participants found no significant effect on primary outcome measures in an intention-to-treat analysis of results from a 24-week trial, although some secondary outcomes were significant.12 A 2-year, randomized, placebo-controlled trial failed to show an effect of rivastigmine (Exelon) on conversion from MCI to dementia.13 Galantamine (Razadyne) in 2 trials was associated with some improvement on secondary measures of cognition but not with any effect on the conversion rate to dementia at 24 months.14 An unexpectedly high galantamine-associated death rate (or perhaps an unexpectedly low placebo-associated death rate) resulted in concern about the balance of galantamine's risks and benefits for patients with MCI.
Memantine (Namenda) has not been reported to benefit patients with MCI. A small, placebo-controlled study of patients with age-associated memory impairment, an MCI-like syndrome, showed no improvement on memory tests but a nonsignificant statistical trend toward improvement on tests of attention and information processing speed.15
Looking ahead, one can certainly hope for pharmacological agents that will offer acute or preventive benefits for at least some patients with MCI. The range of approaches already explored or presently being investigated reflects current interest in a variety of pathophysiological hypotheses that have been explored in small studies with limited or no replication.
One approach to counteracting cognitive impairment would be to try to correct a deficit in neurotransmitters or neuronal components that is hypothesized to be relevant to its pathophysiology. A suspected connection between diminished dopamine D2 receptors and cognitive decline in elderly persons led researchers to administer piribedil, a D2/D3 agonist, to older adults with MCI.16 In this 90-day controlled trial, a significant increase in Mini-Mental State Examination (MMSE) score was noted. Piribedil is a treatment for Parkinson disease that is not readily available in the United States, and its indirect effects on cholinergic function may differentiate it from those available in the United States,17 but perhaps other dopaminergic agonists should be considered for appropriately designed research in patients with MCI.
Although there is still controversy about whether acetylcholinergic function is diminished in MCI as it is in AD,18,19 attempts to boost brain acetylcholine have included administration of cytidine 5'-diphosphocholine (CDP-choline) to older adults with inefficient memory20 or who have mild stages of AD.21 Subsequent studies of CDP-choline have suggested that its mildly beneficial cognitive effects in these patients or others with vascular cognitive impairment reflect its role as an intermediate in the biosynthesis of membrane phospholipids rather than a direct effect on acetylcholine levels.22 Beneficial membrane effects may also explain the observed benefits of the omega-3 fatty acid, docosahexaenoic acid, which were reported by Kotani and associates23 to improve immediate memory and attention in a group of older adults with amnestic MCI.
Among other preliminary leads in treating MCI, one small, 3-month, placebo-controlled trial showed that administration of the calcium channel blocker nimodipine (Nimotop) was associated with improvement in recall and MMSE score.24 In elderly males with age-related cognitive decline and low testosterone levels, a case has been made for testosterone supplementation.25 Additional compounds reported by the Pharmaceutical Research and Manufacturers of America Web site to be in current testing for MCI include vasoactive intestinal peptide (AL-208), a selective metabotropic glutamate receptor antagonist (C-105), a novel L-type calcium channel blocker (MEM-1003), a phosphodiesterase inhibitor (MEM-1414), a g-aminobutyric acid B receptor antagonist (SGS-742), and a selective serotonin receptor (5HT6) antagonist (SGS-518).26 Perhaps the most powerful prophylactic agents will be the promising AD treatments currently in testing as anti-amyloid disease-modifying agents, especially if they prove valuable as early and preventive interventions.27
For Mrs Keyes, in our current state of knowledge, there are important management suggestions that we can make after evaluating her for more definitively treatable causes of cognitive impairment. Lifestyle recommendations should include attention to stress reduction, diet, exercise, and cognitive stimulation. Medical problems such as her hypertension should receive appropriate treatment. Depression, which is common and significant in MCI, should be evaluated and treated as indicated.28 Follow-up cognitive testing at regular intervals will track Mrs Keyes' progress and guide the introduction of other interventions. Of the possible medications that might address cognitive functioning, donepezil, if not the entire class of cholinesterase inhibiting cognitive enhancers, might be regarded as capable of briefly staving off conversion to dementia. The decision to risk its adverse effects in pursuit of a potential benefit would represent an off-label use that is not supported by any formal guidelines or recommendations. As for other medications to improve cognition in MCI or to prevent the development of dementia, they may be just down the road but we are not there yet.
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Winblad B, Palmer K, Kivipelto M, et al. Mild cognitive impairment-beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med. 2004; 156:240-246.
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Devanand DP, Pradhaban G, Liu X, et al. Hippocampal and entorhinal atrophy in mild cognitive impairment: prediction of Alzheimer disease. Neurology. 2007;68:828-836.
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Feldman HH, Ferris S, Winblad B, et al. Effect of rivastigmine on delay to diagnosis of Alzheimer's disease from mild cognitive impairment: the InDDEx study. Lancet Neurol. 2007;6:501-512.
Allain H, BentuÅ½-Ferrer D, Akwa Y. Treatment of the mild cognitive impairment (MCI). Hum Psychopharmacol. 2007;22:189-197.
Ferris S, Schneider L, Farmer M, et al. A double-blind, placebo-controlled trial of memantine in age-associated memory impairment (memantine in AAMI). Int J Geriatr Psychiatry. 2007;22:448-455.
Nagaraja D, Jayashree S. Randomized study of the dopamine receptor agonist piribedil in the treatment of mild cognitive impairment. Am J Psychiatry. 2001;158:1517-1519.
Gobert A, Di Cara B, Cistarelli L, et al. Piribedil enhances frontocortical and hippocampal release of acetylcholine in freely moving rats by blockade of alpha 2A-adrenoceptors: a dialysis comparison to talipexole and quinelorane in the absence of acetylcholinesterase inhibitors. J Pharmacol Exp Ther. 2003:305;338-346.
GrÃ¶n G, Brandenburg I, Wunderlich AP, Riepe MW. Inhibition of hippocampal function in mild cognitive impairment: targeting the cholinergic hypothesis. Neurobiol Aging. 2006;27:78-87.
Herholz K. Acetylcholine esterase activity in mild cognitive impairment and Alzheimer's disease. Eur J Nucl Med Mol Imaging. 2008;35(supp 1):25-29.
Spiers PA, Myers D, Hochanadel GS, et al. Citicoline improves verbal memory in aging. Arch Neurol. 1996;53:441-448.
Alvarez XA, Mouzo R, Pichel V, et al. Double-blind placebo-controlled study with citicoline in APOE genotyped Alzheimer's disease patients. Effects on cognitive performance, brain bioelectrical activity and cerebral perfusion. Methods Find Exp Clin Pharmacol. 1999;21:633-644.
Fioravanti M, Yanagi M. Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly. Cochrane Database Syst Rev. 2005;(2): CD000269.
Kotani S, Sakaguchi E, Warashina S, et al. Dietary supplementation of arachidonic and docosahexaenoic acids improves cognitive dysfunction. Neurosci Res. 2006;56:159-164.
Wang W, Wang LN, Zhang XH, et al. A nimodipine interventional study of patients with mild cognitive impairment [in Chinese]. Zhonghua Nei Ke Za Zhi. 2006;45:274-276.
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Ellison JM, Harper DG, Berlow Y, Zeranski L. Beyond the "C" in MCI: noncognitive symptoms in amnestic and non-amnestic mild cognitive impairment. CNS Spectr. 2008;13:66-72.