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.
Mrs 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
1. Frisoni GB, Canu E, Geroldi C, et al. Drug prescription in mild cognitive impairment: the physicians' perspective in Italy. Int J Geriatr Psychiatry. 2006;21: 1071-1077.
2. Petersen R. Mild cognitive impairment as a diagnostic entity. J Intern Med. 2004;256:183-194.
3. 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.
4. Petersen RC, Doody R, Kurz A, et al. Current concepts in mild cognitive impairment. Arch Neurol. 2001;58:1985-1992.
5. 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.
6. Matsuda H. The role of neuroimaging in mild cognitive impairment. Neuropathology. 2007;27:570-577.
7. Petersen RC, Parisi JE, Dickson DW, et al. Neuropathologic features of amnestic mild cognitive impair- ment. Arch Neurol. 2006;63:665-672.
8. Dickerson BC, Sperling RA, Hyman BT, et al. Clinical prediction of Alzheimer disease dementia across the spectrum of mild cognitive impairment. Arch Gen Psychiatry. 2007;64:1443-1450.
9. Solfrizzi V, Capurso C, D'Introno A, et al. Lifestyle-related factors in predementia and dementia syndromes. Expert Rev Neurother. 2008;8:133-158.
10. Rapp S, Brenes G, Marsh AP. Memory enhancement training for older adults with mild cognitive impairment: a preliminary study. Aging Ment Health. 2002;6:5-11.
11. Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005;352:2379-2388.
12. Salloway S, Ferris S, Kluger A, et al. Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled trial. Neurology. 2004;63:651-657.
13. 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.
14. Allain H, BentuŽ-Ferrer D, Akwa Y. Treatment of the mild cognitive impairment (MCI). Hum Psychopharmacol. 2007;22:189-197.
15. 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.
16. 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.
17. 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.
18. Grön 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.
19. 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.
20. Spiers PA, Myers D, Hochanadel GS, et al. Citicoline improves verbal memory in aging. Arch Neurol. 1996;53:441-448.
21. 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.
22. 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.
23. Kotani S, Sakaguchi E, Warashina S, et al. Dietary supplementation of arachidonic and docosahexaenoic acids improves cognitive dysfunction. Neurosci Res. 2006;56:159-164.
24. 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.
25. Beauchet O. Testosterone and cognitive function: current clinical evidence of a relationship. Eur J Endocrinol. 2006;155:773-781.
26. Pharmaceutical Research and Manufacturers of America. New medicines database. http://newmeds. phrma.org/. Accessed January 12, 2008.
27. Christensen DD. Changing the course of Alzheimer's disease: anti-amyloid disease-modifying treatments on the horizon. Prim Care Companion J Clin Psychiatry. 2007;9:32-41.
28. 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.